Hypocrellin derivative, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a hypocrellin derivative, and a preparation method therefor and the use thereof, wherein the structure of the hypocrellin derivative is as shown in formula (1), formula (2) or formula (1A). Compared with other hypocrellin derivatives, the hypocrellin derivative can be effectively anchored on the surface of a bacterial membrane of a Gram-negative bacterium, achieving high-efficiency photodynamic antibacterial performance. The hypocrellin derivative has broad-spectrum antibacterial and anti-tumor effects, particularly has an excellent photodynamic antibacterial effect on Gram-negative bacterium and Gram-positive bacterium, and also has a photodynamic therapy efficacy on microorganisms such as fungi.

Description

Hypocrellin derivatives and their preparation methods and applications

[0001] This application claims priority to the following two prior applications: Patent Application No. 2024103958463, filed with the State Intellectual Property Office of China on April 2, 2024, entitled “A 14-position cation-substituted hypocrellin derivative, preparation method and use thereof”; and Patent Application No. 2024103958459, filed with the State Intellectual Property Office of China on April 2, 2024, entitled “A polycation-substituted hypocrellin derivative, preparation method and use thereof”. The entire texts of these two prior applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to the technical field of photosensitizer drug photodynamic antibacterial technology, and more specifically to a hypocrellin derivative, a preparation method and application thereof. Background Art

[0003] Antimicrobial drugs generally refer to drugs with bacteriostatic or bactericidal activity. Since the discovery of antimicrobial drugs such as penicillin, they have effectively treated a wide range of bacterial infections. However, due to the overuse of antibiotics and the approaching "post-antibiotic era," bacterial resistance has become a significant threat to global human health. Therefore, there is an urgent need to identify new drugs and approaches that can effectively alleviate this problem. Photodynamic therapy (PDT) is a rapidly developing new broad-spectrum antimicrobial and tumor treatment technology in recent years. Due to its advantages such as excellent selectivity, minimal toxicity and side effects, minimal invasiveness, broad antitumor spectrum, good applicability, easy elimination of latent cancer lesions, repeatable treatment, and minimal side effects, it has become one of the most promising treatments for drug-resistant bacterial infections. During PDT, a photosensitizer absorbs photon energy under illumination, transitioning from the ground state to a singlet excited state, and then to a triplet excited state via intersystem crossing. Photosensitizers in the triplet excited state can generate reactive oxygen species (ROS) through two mechanisms: (1) the photosensitizer molecules in the triplet excited state undergo electron transfer or hydrogen abstraction reaction with the solvent or substrate to form free radicals or cation or anion radicals, which then combine with oxygen to produce hydroxyl radicals or superoxide anions; (2) energy transfer occurs between the photosensitizer molecules in the triplet excited state and oxygen to produce singlet oxygen ( 1 O2). The generated ROS react with the bacterial membrane or biomacromolecules within the bacteria, inducing bacterial death. The interaction between a suitable light source, a photosensitizer, and oxygen is the three main factors in achieving PDT, with the photosensitizer being the key factor influencing PDT's effectiveness.

[0004] Although existing photosensitizers, such as first-generation photosensitizers hematoporphyrin derivatives; second-generation photosensitizers porphyrins, phthalocyanines, and perylenequinones, have excellent photodynamic antibacterial effects on Gram-positive bacteria, most photosensitizers have poor solubility and, more importantly, limited photodynamic antibacterial effects on Gram-negative bacteria. The main reasons are: compared with Gram-positive bacteria, the thicker outer membrane structure of Gram-negative bacteria hinders the entry of photosensitizers into the bacteria, and the lifespan and distance of ROS generated by photosensitizers under light conditions are very short, making it impossible to effectively perform photodynamic therapy on Gram-negative bacteria. In recent years, researchers have adopted methods such as (1) introducing cations into photosensitizers through chemical modification; (2) co-assembling photosensitizers with cationic polymers; and (3) combining photosensitizers with cationic antimicrobial peptides to improve the problem of poor efficacy against Gram-negative bacteria.

[0005] Hypocrellin is a natural photosensitizer extracted from Hypocrellin, a parasitic fungus found on the arrow bamboo at an altitude of 4,000 meters on the Yunnan Plateau in my country. It has been used as a traditional Chinese medicine for centuries, boasting benefits such as clearing heat, detoxifying, and dispelling carbuncle. Its main components include Hypocrellin A (HA) and Hypocrellin B (HB). As a second-generation photosensitizer, Hypocrellin offers advantages such as easy extraction, high singlet oxygen yield, rapid metabolism, and no side effects. However, its hydrophobicity limits its application in photodynamic therapy. Furthermore, like most photosensitizers, Hypocrellin exhibits excellent photodynamic antibacterial activity against Gram-positive bacteria but is unable to effectively kill Gram-negative bacteria. Although numerous chemical modifications of Hypocrellin have been conducted over the past decade, amphiphilic Hypocrellin derivatives with long wavelengths (600-700 nm) have been developed. However, the currently prepared hypocrellin derivatives still face the problem of poor photodynamic efficacy against Gram-negative bacteria. Therefore, it is of great research significance to prepare new hypocrellin derivatives to improve their bacterial targeting and enhance their photodynamic antibacterial effect. Summary of the Invention

[0006] In view of the problem that existing hypocrellin derivatives have poor photodynamic effects on Gram-negative bacteria, one object of the present invention is to provide a hypocrellin derivative.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned hypocrellin derivatives.

[0008] The third object of the present invention is to provide applications of the above-mentioned hypocrellin derivatives.

[0009] In order to achieve the above first object, the present invention adopts the following technical solutions:

[0010] A hypocrellin derivative or an isomer thereof represented by formula (1), formula (2) or formula (1A):

[0011] In formula (1) or (2), R1 is H or COCH3; C 13 、C 14 and C 15 The dotted line indicates that the double bond is located at C 13 =C 14 or C 14 =C 15 , and C 13 、C 14 and C 15 There is only one double bond between

[0012] In formula (1), the dotted line of T1 indicates that R4 and R5 are connected or not connected. When R4 and R5 are connected, they, together with the C at the 2' and 3' positions, form the following group which is unsubstituted or substituted by one, two or more Ra: C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; wherein T1 is unsubstituted or substituted C3-C 12 A linker obtained by removing the 2' and 3' carbon atoms from a cycloalkyl or 3-12 membered heterocyclic group;

[0013] Ra is selected from R, C1-C 12 Alkyl, C1-C 12 Alkoxy, hydroxy, thiol, carboxyl, amino or sulfonic acid groups;

[0014] When R4 and R5 are not connected, R3, R4, R5 and R6 are the same or different and are independently selected from H, R, Cl-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, oxa C2-C 12 Alkyl, hydroxyl, thiol, carboxyl, sulfonic acid or glycol acetal groups;

[0015] R2 and R7 are the same or different and are independently selected from H, C1-C 12 Alkyl, C1-C 12 Alkoxy, halogenated C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C6-C 12 Aryl, -C1-C 12 Alkyl-C6-C 12 Aryl, 3-12 membered heterocyclic group, hydroxyl, thiol, carboxyl, sulfonic acid, oxaC2-C 10 Alkyl or glycol group; the -C1-C 12 Alkyl-C6-C 12The aryl group of the aryl group is optionally substituted by one, two or more Rb, Rb is selected from the following groups: C1-C 12 Alkyl, C1-C 12 Alkoxy or -C1-C 12 Alkyl-N + (C1-C 12 alkyl)3;

[0016] In formula (2), the dotted line of T2 represents two adjacent R8 and R9, R 10 With R 11 Connected or not connected; when two adjacent R8 and R9, or R 10 and R 11 When not connected, R8 and R 11 OH, R9 and R 10 is H;

[0017] When two adjacent R8 and R9 are linked together, R8 and R9, together with T2 and positions 4 and 5, form a saturated or unsaturated six-membered heterocyclic ring substituted or unsubstituted by one, two or more Rc, wherein T2 is a linker between R8 and R9;

[0018] When two adjacent R 10 With R 11 When connected, R 10 and R 11 Together with T2 and positions 8 and 9, it forms a saturated or unsaturated six-membered heterocyclic ring substituted or unsubstituted by one, two or more Rc, wherein T2 is R 10 and R 11 The connector between

[0019] Rc is selected from C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, carboxyl, -COO-C1-C 12 Alkyl, -CONH-C1-C 12 Alkyl, oxaC2-C 12 Alkyl, R, aldehyde, hydroxyl, thiol, carboxyl, sulfonic acid, glycol acetal, C3-C 12 Cycloalkyl, C6-C 12 Aryl or 3-12 membered heterocyclic group;

[0020] In formula (1) or (2), R is the same or different, and the general structural formula is shown in formula (3):

[0021] In formula (3), t and u are independently selected from integers from 0 to 15, r is 0 or 1, and s is 0 or 1; v are the same or different and are independently selected from integers from 0 to 6;

[0022] In formula (3), the linking groups X and Y are the same or different and are independently -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -C(=O)-, -CH=CH-, -C≡C-, -SO3-, -N + (R 20 )(R 21 )-、-NHCO-C3-C 12 Cycloalkyl-; unsubstituted or optionally substituted by Rk: -C3-C 12 Cycloalkenyl-, -C3-C 12 Cycloalkyl-, -C6-C 12 Aryl-, -3-12 membered heterocyclic-; said Rk is selected from C1-C 12 Alkyl, carboxyl, amino, hydroxyl, -COOC1-C 12 Alkyl or -C1-C 12 Alkyl-COOH;

[0023] In formula (3), J and K are the same or different and are independently a quaternary ammonium salt cation, and the general structural formula thereof is shown in (4-1) or (4-2):

[0024] In formula (4-1), E is N or P; in formulas (4-1) and (4-2), m, m1, n, and n1 are independently selected from integers of 0 to 15, and p and q are independently selected from integers of 0 to 12;

[0025] The conditions are:

[0026] When J is selected from formula (4-1) and K is selected from formula (4-2), p and q are not 0 at the same time; or,

[0027] When K is selected from formula (4-1) and J is selected from formula (4-2), p and q are not 0 at the same time; or,

[0028] When J and K are both selected from formula (4-1), the two ps are not 0 at the same time; or,

[0029] When J and K are selected from formula (4-2) at the same time, the two qs are not 0 at the same time;

[0030] In formula (3), the terminal group Z is selected from hydrogen, hydroxyl, carboxyl, amino, thiol, sulfonic acid, C1-C 12 Alkyl, C1-C 12 Alkoxy, -COOC1-C 12 Alkyl, oxaC2-C 12 Alkyl; C3-C substituted with one, two or more Rd 12 Cycloalkyl or 3-12 membered heterocyclic group; j = 1-60 (e.g. 1-30); C6-C ... 12 Aryl; unsubstituted or substituted with one, two or more Rf pyridinium salts -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 );

[0031] Rd, Re, and Rf are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C 12 Alkyl, C1-C 12 Alkyl, -C1-C 12 Alkyl-OH, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 6-12 membered aryl; or one, two or more hydroxyl, carboxyl, sulfonic acid or -COOC1-C 12 Alkyl-substituted C1-C 12 alkyl;

[0032] R 12 、R 13 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 The same or different, each independently being unsubstituted or optionally substituted by one, two or more Rg: C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 12 Aryl, C6-C 12 Aryl-C1-C 12 Alkyl-, oxaC2-C 12 Alkyl, aza C2-C 12 Alkyl or thia C2-C 12 alkyl;

[0033] Rg is selected from hydroxyl, carboxyl, sulfonic acid or carboxylate groups (-COOC1-C 12 alkyl);

[0034] In formula (1) or (2), the anion paired with the cation in group R is any pharmaceutically acceptable anion;

[0035] In formula (1A), R 1a is H or COCH3;

[0036] C 13 、C 14 and C 15 The dotted line indicates that the double bond is located at C 13 =C 14 or C 14 =C 15 , and C 13 、C 14 and C 15 There is only one double bond between

[0037] R 2a Selected from -NH-C1-C 12 Alkyl, -NH-C3-C 12 Cycloalkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl, -NH-(O hetero C2-C 12 Alkyl), -NH-(CH2CH2O) j -CH3, j = 1-60, -NH-C1-C 12 Alkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-COOH, -NH-(O hetero C2-C 12 Alkyl)-R', -NH-(O and N hetero C4-C 12 Alkyl), -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl-C1-C 12 Alkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-OH, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-R', -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-R', -NH-(O and N hetero C4-C 12 alkyl)-R';

[0038] R 3a and R 4a The same or different, independently selected from R', OH, -NH-C1-C 12 Alkyl, -NH-C3-C 12 Cycloalkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl, -NH-(O hetero C2-C 12 Alkyl), -O-C1-C 12 Alkyl-R', -NH-C1-C 12 Alkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-C1-C 12 Alkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-OH, -NH-(O hetero C2-C 12 Alkyl)-R', -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl-R', -NH-(O and N hetero C4-C 12 alkyl)-R';

[0039] R 5a Selected from R' or methyl;

[0040] The condition is R 2a 、R 5a At least one group is R' or a substituent containing R';

[0041] The structure of R' is shown in formula (3A):

[0042] In formula (3A), J' and K' are the same or different and are independently a quaternary ammonium salt cation, and the general structure thereof is shown in (4-1A) or (4-2A):

[0043] In formula (4-1A), E is N or P;

[0044] In formulas (4-1A) and (4-2A), m, m1, n, and n1 are independently selected from integers of 0 to 15, and p' and q' are independently selected from integers of 0 to 12;

[0045] In formula (3A), t' and u' are independently selected from integers from 0 to 15; r' is 0 or 1, s' is 0 or 1; v' are the same or different and are independently selected from integers from 0 to 6;

[0046] The linking groups X' and Y' are the same or different and are each independently -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -C(=O)-, -CH=CH-, -C≡C-, -SO3-, -N + (R 20 )(R 21 )-、-NHCO-C3-C 12 Cycloalkyl-, unsubstituted or optionally substituted by Rk': -C3-C 12 Cycloalkenyl-, -C3-C 12 Cycloalkyl-, -C6-C 12 Aryl-, -3-12 membered heterocyclic-; said Rk' is selected from C1-C 12 Alkyl, carboxyl, amino, hydroxyl, -COOC1-C 12 Alkyl or -C1-C 12 Alkyl-COOH;

[0047] The terminal group Z' is selected from hydrogen, hydroxyl, carboxyl, amino, mercapto, sulfonic acid (-SO3H), C1-C 12 Alkyl, C1-C 12 Alkoxy, -COOC1-C 12 Alkyl, oxaC2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd' C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; j = 1-60 (eg 1-30); C6-C substituted with one, two or more Re' 12 Aryl; unsubstituted or substituted by one, two or more Rf ' substituted pyridinium salt (eg ), -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 );

[0048] Rd', Re', Rf' are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C 12 Alkyl, C1-C 12 Alkyl, -C1-C12 Alkyl-OH, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 6-12 membered aryl; or one, two or more hydroxyl, carboxyl, sulfonic acid or -COOC1-C 12 Alkyl-substituted C1-C 12 alkyl;

[0049] R 12 、R 13 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 The same or different, each independently being unsubstituted or optionally substituted by one, two or more Rg: C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 12 Aryl, C6-C 12 Aryl-C1-C 12 Alkyl-, oxaC2-C 12 Alkyl, aza C2-C 12 Alkyl or thia C2-C 12 alkyl;

[0050] Rg is selected from hydroxyl, carboxyl, sulfonic acid or -COOC1-C 12 alkyl;

[0051] Furthermore, formula (3A) contains at least two groups with cations;

[0052] In formula (1A), the anion paired with the cation in group R' is any pharmaceutically acceptable anion.

[0053] According to an embodiment of the present invention, the isomer is an enol tautomer.

[0054] According to an embodiment of the present invention, in formula (3), t and u are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0055] v is selected from 0, 1, 2, 3 or 4.

[0056] According to an embodiment of the present invention, the linking groups X and Y in formula (3) are the same or different and are independently -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -SO3-, -N + (R 20 )(R 21 )-, -NHCO-C3-C6 cycloalkyl-;

[0057] According to an embodiment of the present invention, the terminal group Z in formula (3) is selected from hydrogen, hydroxyl, carboxyl, amino, mercapto, sulfonic acid, C1-C6 alkyl, C1-C6 alkoxy, -COOC1-C6 alkyl, oxa-C2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd C3-C6 cycloalkyl or 3-6 membered heterocyclic group; j = 1-10; phenyl which is unsubstituted or substituted by one, two or more Re; pyridinium salt which is unsubstituted or substituted by one, two or more Rf (e.g. -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ); where R 22 、R 23 、R 24 、R 25 、R 26 、R 27 The same or different, each independently a C1-C6 alkyl or a phenyl group; for example -N + (R 22 )(R 23 )(R 24 ) is trimethylammonium salt -P + (R 25 )(R 26 )(R 27 ) is trimethylphosphonium salt or triphenylphosphonium salt

[0058] According to an embodiment of the present invention, Rd, Re, and Rf are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C6 alkyl, C1-C6 alkyl, or -C1-C6 alkyl-OH;

[0059] According to an embodiment of the present invention, R 12 、R 13 、R 20 、R21 are the same or different, and are each independently C1-C6 alkyl, oxa-C2-C6 alkyl, aza-C2-C6 alkyl or thia-C2-C6 alkyl.

[0060] According to an embodiment of the present invention, in formula (4-1) and (4-2), m, m1, n, n1 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p and q are independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0061] According to an embodiment of the present invention, the formula (3) may be, for example, as shown in (5-1) or (5-2) below:

[0062] Among them, v, X, Y, r, m, m1, n, n1, R 12 、R 13 , q, p, s, u, t, Z have the definitions as described above;

[0063] In (5-1) or (5-2), p and q are not 0 at the same time.

[0064] According to an embodiment of the present invention, in formula (2), when R8 is connected to R9, the six-membered heterocyclic ring contains two heteroatoms, which are the same or different and are optionally N or S.

[0065] According to an embodiment of the present invention, in formula (2), when R 10 With R 11 When connected, the six-membered heterocyclic ring contains two heteroatoms, which are the same or different and are optionally N or S.

[0066] According to an embodiment of the present invention, when the terminal group Z is a pyridinium salt, the substituent Rf of the pyridinium salt is substituted at the ortho position, meta position or para position of pyridine.

[0067] According to an embodiment of the present invention, the anion paired with the cation is a pharmaceutically acceptable anion, such as a halide ion (F, Cl, Br, I), a sulfate ion, a phosphate ion, a sulfonate ion, and the like.

[0068] According to an embodiment of the present invention, when R4 and R5 are not connected, R3, R4, R5 and R6 are the same or different and are independently selected from H, C1-C6 alkyl, -halo-C1-C6 alkyl, C1-C6 alkoxy or oxa-C2-C6 alkyl. 10 alkyl.

[0069] According to an embodiment of the present invention, when R4 and R5 are connected, R4, R5 and T1 form the following ring system which is substituted or unsubstituted by one or two Ra: a five-membered ring, a six-membered ring or a seven-membered ring, the structure of which is shown in formula (4),

[0070] wherein ring A is a saturated or unsaturated five-membered, six-membered, or seven-membered heterocyclic group; or a five-membered, six-membered, or seven-membered cycloalkyl group, for example, A is a six-membered cycloalkyl group;

[0071] Ra is selected from C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkyl.

[0072] According to an embodiment of the present invention, R2 and R7 are the same or different and are independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C1-C6 alkyl-phenyl, 3-6 membered heterocyclic group, hydroxyl, thiol, carboxyl, sulfonic acid, glycol acetal or oxa-C2-C 10 Alkyl; the phenyl group in the -C1-C6 alkyl-phenyl group is optionally substituted by one, two or more Rb, Rb being selected from the following groups: C1-C 10 Alkyl, C1-C6 alkoxy or -C1-C 10 Alkyl-N + (C1-C6 alkyl)3.

[0073] According to an embodiment of the present invention, R2 and R7 are the same or different and are independently selected from H, -C1-C6 alkyl-phenyl, -C1-C6 alkyl-phenyl-C1-C 10 Alkyl-N + (C1-C6 alkyl)3, -C1-C6 alkyl-phenyl-C1-C 10 Alkyl, oxaC2-C 10 alkyl.

[0074] According to an embodiment of the present invention, m, ml, n, n1, t, u are independently selected from 0, 1, 2, 3, 4, 5 or 6; v are independently selected from 0, 1 or 2; p, q are independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0075] According to an embodiment of the present invention, when R8 and R9 are not linked, R8 is OH and R9 is H.

[0076] According to an embodiment of the present invention, when R 10 and R 11 When not connected, R 11 OH, R 10 For H.

[0077] According to an embodiment of the present invention, when R8 is connected to R9, and / or R 10 With R 11 When connected, R8, R9 and T2, as well as R 10 、R 11and T2 independently form a structure as shown in formula (5) or formula (6),

[0078] Among them, the substituent R 14 、R 15 、R 16 、R 17 、R 18 The same or different, independently selected from hydrogen, C1-C6 alkyl, -COO-C1-C6 alkyl, oxa-C2-C 10 Alkyl, C1-C6 alkoxy, hydroxyl, mercapto, carboxyl, sulfonic acid, glycol or R.

[0079] According to an embodiment of the present invention, the linking groups X and Y are the same or different and are each independently -N + (CH3)2-, -C=N-, -NH-, -O-, -S-, -COO-, -OCO-, -SO3-, -CONH-, -NHCO-, -NHCO-cyclopropyl-, -NHCO-cyclobutyl-, -NHCO-cyclopentyl-, -NHCO-cyclohexyl-, -C(=O)-, -CH=CH-, -C≡C-, -cyclopropyl-, -cyclobutyl-, -cyclopentyl-, -C5H7(CH3)-<methylcyclopentylidene>, -C5H7(OH)-<hydroxycyclopentylidene>, -C5H7(NH2)-<aminocyclopentylidene>, -C6H 10 -<cyclohexylene>, -C6H9(CH3)-<methylcyclohexylene>, -C6H9(C2H5)-<ethylcyclohexylene>, -C6H9(C3H7)-<propylcyclohexylene>, -C6H9(C4H9)-<butylcyclohexylene>, -C6H8(CH3)2-<dimethylcyclohexylene>, -C6H9(OH)-<hydroxycyclohexylene>, -C6H9(NH2)-<aminocyclohexylene>, -C6H9(COOH)-<carboxycyclohexylene>, -C6H9(CH2COOH)-<carboxymethylcyclohexylene>, -C6H9(C2H5COOH)-<carboxyethylcyclohexylene>, -cycloheptyl-, -phenyl-, -pyridyl-, -C5H2N(CH3)-<methylpyridylene>,

[0080] According to an embodiment of the present invention, the terminal group Z is selected from: -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 、-C6H 13 , -C6H5, -C5H4N, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 、-OC6H 13、-OH、-NH2、-SH、-COOH、-COOCH3、-COOC2H5、-SO3H、cycloalkyl、 j = 1-6;

[0081] According to an exemplary embodiment of the present invention, the hypocrellin derivative represented by formula (1) or formula (2) is selected from the compounds shown below:

[0082] It is well known to those skilled in the art that the parent hypocrellin also has enol tautomers, so the protection scope of the present application also includes the enol tautomer (1') of formula (1); or, the enol tautomer (2') of formula (2); or, the enol tautomer (1A') of formula (1A):

[0083] Here, each group and dashed line have the same definitions as above.

[0084] The present invention also provides a method for preparing a hypocrellin derivative as shown in the above formula (1) or formula (2), comprising the following steps:

[0085] Formula (1-1) or formula (2-1) and cationic derivative R X -L1 reaction to obtain a hypocrellin derivative represented by formula (1) or formula (2);

[0086] Where Lx is (CH2) V L', L' is CHO, OH, COOH, NH2 or Br;

[0087] When L' is CHO, R X Selected from Wherein X is NH, L1 is H, and r is 1;

[0088] When L' is OH or NH2, R X Selected from wherein X is C(O), L1 is OH, and r is 1; or, when L' is OH, X is S or O, L is H, and r is 1;

[0089] When L' is COOH, R X Selected from wherein X is O, L1 is H, and r is 1; or X is NH, L1 is H, and r is 1;

[0090] When L' is Br, R X Selected from Where X is N(R 20 )(R 21 ), L1 does not exist, r is 1;

[0091] The other groups and dashed lines have the same definitions as above.

[0092] According to an embodiment of the present invention, the reaction for preparing the hypocrellin derivative represented by formula (1) or formula (2) is carried out under the protection of an inert gas and in the absence of light.

[0093] According to an embodiment of the present invention, the reaction time for preparing the hypocrellin derivative represented by formula (1) or formula (2) is 3-120 hours; and the reaction temperature is 40-100°C.

[0094] According to an embodiment of the present invention, the reaction for preparing the hypocrellin derivative represented by formula (1) or formula (2) is carried out in an organic solvent, and the organic solvent is acetonitrile, tetrahydrofuran, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, methanol or ethanol.

[0095] According to an embodiment of the present invention, the method for preparing the hypocrellin derivative represented by formula (1) or formula (2) further comprises a reaction purification step, wherein the crude product is subjected to column chromatography.

[0096] According to an embodiment of the present invention, in formula (1A), R 1a is H or COCH3;

[0097] The R 2a Selected from -NH-C1-C6 alkyl, -NH-C3-C6 cycloalkyl, -NH-C1-C6 alkyl-C3-C6 cycloalkyl, -NH-(O hetero C2-C6 alkyl), -NH-C1-C6 alkyl-R', -NH-C1-C6 alkyl-phenyl, -NH-C1-C6 alkyl-C3-C6 cycloalkyl-COOH, -NH-(O hetero C2-C6 alkyl)-R', -NH-(O and N hetero C4-C6 alkyl), -NH-C1-C6 alkyl-C3-C6 cycloalkyl-R', -NH-C1-C6 alkyl-phenyl-C 1-6 Alkyl, -NH-C1-C6 alkyl-C3-C6 cycloalkyl-OH, -NH-C1-C6 alkyl-phenyl-R';

[0098] R 5a is selected from R' or methyl.

[0099] According to an embodiment of the present invention, formula (3A) contains at least two groups carrying cations, for example, contains 2, 3, 4, 5, 6, 7 or 8 groups carrying cations.

[0100] According to an embodiment of the present invention, the group with a cation in formula (3A) is, for example Pyridinium salts, unsubstituted or substituted by one, two or more Rf', -N + (R 20 )(R 21 )-、-N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ).

[0101] In some embodiments, when Z' in formula (3A) is a group with a cation, such as a pyridinium salt which is unsubstituted or substituted with one, two or more Rf', -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ), then at least one of J' and K' is a group with a cation, that is:

[0102] In formula (3A), when J' is selected from formula (4-1A), K' is selected from formula (4-2A), p' and q' are not both 0; or,

[0103] In formula (3A), when K' is selected from formula (4-1A) and J' is selected from formula (4-2A), p' and q' are not both 0; or,

[0104] In formula (3A), when J' and K' are both selected from formula (4-1A), the two p's are not 0 at the same time; or,

[0105] In formula (3A), when J' and K' are both selected from formula (4-2A), the two q's are not simultaneously 0;

[0106] In some embodiments, when Z' in formula (3A) is a group without a cation, such as hydrogen, hydroxyl, carboxyl, amino, thiol, sulfonic acid (-SO3H), C1-C 12 Alkyl, C1-C 12 Alkoxy, -COOC1-C 12 Alkyl, oxaC2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd' C3-C12 Cycloalkyl or 3-12 membered heterocyclic group; Then at least two of J' and / or K' are groups with cations, that is:

[0107] In formula (3A), when J' is selected from formula (4-1A) and K' is selected from formula (4-2A), p'+q' is greater than or equal to 2; or,

[0108] In formula (3A), when K' is selected from formula (4-1A) and J' is selected from formula (4-2A), p'+q' is greater than or equal to 2; or,

[0109] In formula (3A), when J' and K' are both selected from formula (4-1A), the sum of the two p's is greater than or equal to 2; or,

[0110] In formula (3A), when J' and K' are both selected from formula (4-2A), the sum of the two q' is greater than or equal to 2;

[0111] According to an embodiment of the present invention, m, m1, n, n1, t', u' in (4-1A) and (4-2A) are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; j = 1-30; or for example, j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0112] p' and q' are independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; v' is selected from 0, 1, 2, 3 or 4.

[0113] According to an embodiment of the present invention, the formula (3A) may be, for example, as shown below (5-1A) or (5-2A):

[0114] Among them, v', X', Y', r', m, m1, n, n1, R 12 、R 13 , q', p', s', u', t', Z' have the definitions as described above;

[0115] Formula (5-1A) or (5-2A) contains at least two groups with cations.

[0116] According to an embodiment of the present invention, the linking groups X' and Y' in formula (3A) are the same or different and are each independently -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -SO3-, -N + (R 20 )(R 21 )-, -NHCO-C3-C6 cycloalkyl-;

[0117] According to an embodiment of the present invention, the terminal group Z' in formula (3A) is selected from hydrogen, hydroxyl, carboxyl, amino, mercapto, sulfonic acid, C1-C6 alkyl, C1-C6 alkoxy, -COOC1-C6 alkyl, oxa-C2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd' C3-C6 cycloalkyl or 3-6 membered heterocyclic group; j = 1-10; phenyl which is unsubstituted or substituted by one, two or more Re'; pyridinium salt which is unsubstituted or substituted by one, two or more Rf' (eg ), -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ); where R 22 、R 23 、R 24 、R 25 、R 26 、R 27 The same or different, each independently a C1-C6 alkyl or a phenyl group; for example -N + (R 22 )(R 23 )(R 24 ) is trimethylammonium salt -P + (R 25 )(R 26 )(R 27 ) is trimethylphosphonium salt or triphenylphosphonium salt

[0118] According to an embodiment of the present invention, Rd', Re', Rf' are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C6 alkyl, C1-C6 alkyl or -C1-C6 alkyl-OH;

[0119] According to an embodiment of the present invention, R in (4-1A) and (4-2A) 12 、R 13 、R 20 、R 21 are the same or different and are independently C1-C6 alkyl, oxa-C2-C6 alkyl, aza-C2-C6 alkyl or thia-C2-C6 alkyl.

[0120] According to an embodiment of the present invention, when the terminal group Z' in formula (3A) is a pyridinium salt, the substituent Rf' of the pyridinium salt is substituted at the ortho position, meta position or para position of pyridine.

[0121] According to an embodiment of the present invention, the anion paired with the cation in formula (1A) is a pharmaceutically acceptable anion, such as a halide ion (F, Cl, Br or I), a sulfate ion, a phosphate ion, a sulfonate ion, and the like.

[0122] According to an embodiment of the present invention, the linking groups X' and Y' in formula (3A) are the same or different and are each independently -N + (CH3)2-, -C=N-, -NH-, -O-, -S-, -COO-, -OCO-, -SO3-, -CONH-, -NHCO-, -NHCO-cyclopropyl-, -NHCO-cyclobutyl-, -NHCO-cyclopentyl-, -NHCO-cyclohexyl-, -C(=O)-, -CH=CH-, -C≡C-, -cyclopropyl-, -cyclobutyl-, -cyclopentyl-, -C5H7(CH3)-<methylcyclopentylidene>, -C5H7(OH)-<hydroxycyclopentylidene>, -C5H7(NH2)-<aminocyclopentylidene>, -C6H 10 -<cyclohexylene>, -C6H9(CH3)-<methylcyclohexylene>, -C6H9(C2H5)-<ethylcyclohexylene>, -C6H9(C3H7)-<propylcyclohexylene>, -C6H9(C4H9)-<butylcyclohexylene>, -C6H8(CH3)2-<dimethylcyclohexylene>, -C6H9(OH)-<hydroxycyclohexylene>, -C6H9(NH2)-<aminocyclohexylene>, -C6H9(COOH)-<carboxycyclohexylene>, -C6H9(CH2COOH)-<carboxymethylcyclohexylene>, -C6H9(C2H5COOH)-<carboxyethylcyclohexylene>, -cycloheptyl-, -phenyl-, -pyridyl-, -C5H2N(CH3)-<methylpyridylene>,

[0123] According to an embodiment of the present invention, the terminal group Z' in formula (3A) is selected from: -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 、-C6H 13 , -C6H5, -C5H4N, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 、-OC6H 13 、-OH、-NH2、-SH、-COOH、-COOCH3、-COOC2H5、-SO3H、cycloalkyl、 j = 1-6;

[0124] According to an embodiment of the present invention, in formula (1A), R 1a is H or COCH3;

[0125] The R 2a Selected from -NH-C1-C3 alkyl, -NH-C3-C6 cycloalkyl, -NH-C1-C3 alkyl-C3-C6 cycloalkyl, -NH-(O hetero C2-C6 alkyl), -NH-C1-C3 alkyl-R', -NH-C1-C3 alkyl-phenyl, -NH-C1-C3 alkyl-C3-C6 cycloalkyl-COOH, -NH-(O hetero C2-C6 alkyl)-R', -NH-(O and N hetero C4-C6 alkyl), -NH-C1-C6 alkyl-C3-C6 cycloalkyl-R', -NH-C1-C6 alkyl-phenyl-C 1-3 Alkyl, -NH-C1-C3 alkyl-C3-C6 cycloalkyl-OH, -NH-C1-C6 alkyl-phenyl-R', -NH-C1-C6 alkyl-C3-C6 cycloalkyl-R', -NH-(O and N hetero C4-C6 alkyl)-R';

[0126] R 5a is selected from R' or methyl.

[0127] According to an exemplary embodiment of the present invention, the hypocrellin derivative represented by formula (1A) is selected from the compounds shown below:

[0128] The present invention also provides a method for preparing the compound represented by formula (1A), comprising the following steps:

[0129] Compound (1-1A) and polycationic derivative R y -L2 reaction to obtain the hypocrellin derivative represented by formula (1A);

[0130] R2' is selected from -NH-C1-C 12 Alkyl, -NH-C3-C 12 Cycloalkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl, -NH-(O hetero C2-C 12 Alkyl), -NH-(CH2CH2O) j -CH3, j = 1-60, -NH-C1-C 12 Alkyl-L, -NH-C1-C 12 Alkyl-C6-C 12Aryl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-COOH, -NH-(O hetero C2-C 12 Alkyl)-L, -NH-(O and N hetero C4-C 12 Alkyl), -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-L, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-C1-C 12 Alkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-OH, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-L, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-L, -NH-(O and N hetero C4-C 12 alkyl)-L;

[0131] R3' and R4' are the same or different and are independently selected from L, OH, -NH-C1-C 12 Alkyl, -NH-C3-C 12 Cycloalkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl, -NH-(O hetero C2-C 12 Alkyl), -NH-(CH2CH2O) j -CH3, j = 1-60, -O-C1-C 12 Alkyl-L, -NH-C1-C 12 Alkyl-L, -NH-C1-C 12 Alkyl-C6-C 12 Aryl, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-C1-C 12 Alkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-OH, -NH-(O hetero C2-C 12 Alkyl)-L, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-L, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-L, -NH-(O and N hetero C4-C 12 alkyl)-L;

[0132] R5' is selected from L or methyl;

[0133] L is (CH2) V’ L', L' is CHO, OH, COOH, NH2 or Br;

[0134] When L' is CHO, R y Selected from Wherein X' is NH, L2 is H, and r' is 1;

[0135] When L' is OH or NH2, R y Selected from wherein X' is C(O), L2 is OH, and r' is 1; or, when L' is OH, X' is S or O, L2 is H, and r' is 1;

[0136] When L' is COOH, R y Selected from wherein X' is O, L2 is H, and r' is 1; or X' is NH, L2 is H, and r' is 1;

[0137] When L' is Br, R y Selected from Where X' is N(R 20 )(R 21 ), L2 does not exist, r' is 1;

[0138] The other groups and dashed lines have the same definitions as above.

[0139] According to an embodiment of the present invention, the reaction for preparing the hypocrellin derivative represented by formula (1A) is carried out under the protection of an inert gas and in the absence of light.

[0140] According to an embodiment of the present invention, the reaction time for preparing the hypocrellin derivative represented by formula (1A) is 3-120 hours; and the reaction temperature is 40-100°C.

[0141] According to an embodiment of the present invention, the reaction for preparing the hypocrellin derivative represented by formula (1A) is carried out in an organic solvent, which is acetonitrile, tetrahydrofuran, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, methanol or ethanol.

[0142] According to an embodiment of the present invention, the method for preparing the hypocrellin derivative represented by formula (1A) further comprises a reaction purification step, wherein the crude product is subjected to column chromatography.

[0143] The present invention also provides a pharmaceutical composition comprising a hypocrellin derivative or an isomer thereof as shown in the above formula (1), formula (2) or formula (1A).

[0144] According to an embodiment of the present invention, the pharmaceutical composition is a photosensitizer drug, which is used to treat cancer, or to inhibit or kill bacteria.

[0145] The present invention also provides the use of the hypocrellin derivatives or isomers thereof represented by the above formula (1), formula (2) or formula (1A) in the preparation of photodynamic therapy drugs.

[0146] According to an embodiment of the present invention, the photodynamic therapy drug is a photosensitizer drug.

[0147] According to an embodiment of the present invention, the photosensitizer drug is used to treat cancer, such as cervical cancer, skin squamous cell carcinoma, esophageal cancer or bile duct cancer.

[0148] According to an embodiment of the present invention, the photosensitizer drug is used for bacteriostasis or bactericidal purposes, for example, for inhibiting or killing Gram-negative bacteria, Gram-positive bacteria or fungi.

[0149] According to an embodiment of the present invention, the photosensitizer drug is used to inhibit or kill the following bacteria: Escherichia coli, Pseudomonas aeruginosa, Proteus, Salmonella typhi, Bordetella pertussis, Salmonella, Klebsiella, Neisseria meningitidis, Staphylococcus aureus; or to inhibit or kill the following fungi: Candida albicans, Mucor.

[0150] The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least one of the hypocrellin derivatives represented by formula (1), formula (2) or formula (1A) or their isomers.

[0151] The present invention also provides a bacteriostatic or bactericidal method, which comprises administering to a subject a therapeutically effective amount of at least one of the hypocrellin derivatives represented by formula (1), formula (2) or formula (1A) or their isomers.

[0152] According to an embodiment of the present invention, the method is performed under light irradiation, preferably under ultraviolet light irradiation. The subject is, for example, a mammal, such as a human.

[0153] The beneficial effects of the present invention are as follows:

[0154] 1) The raw materials of the hypocrellin in the present invention are extracted from natural products, which are easily available, low in cost, can be prepared in large quantities, have little toxicity and side effects, and are easy to metabolize.

[0155] 2) Compared to other hypocrellin derivatives, the hypocrellin derivatives prepared in this invention can effectively anchor on the surface of Gram-negative bacterial membranes, achieving efficient photodynamic antibacterial properties. The prepared hypocrellin derivatives can efficiently generate reactive oxygen species (primarily singlet oxygen, supplemented by other reactive oxygen species such as superoxide radicals) under light irradiation.

[0156] 3) Compared with the first- and second-generation porphyrin and phthalocyanine photosensitizers used clinically, the hypocrellin derivative photosensitizer of the present invention has a clear structure and is easy to separate and purify, overcoming the problems of porphyrin and phthalocyanine photosensitizers that are difficult to separate and have complex structures that are difficult to determine.

[0157] 4) The hypocrellin derivatives of the present invention have broad-spectrum antibacterial and antitumor effects, especially excellent photodynamic antibacterial effects on both Gram-negative and Gram-positive bacteria, and also have photodynamic therapeutic effects on microorganisms such as fungi.

[0158] Definitions and Explanations of Terms

[0159] Some substituents Indicates the connection site.

[0160] In this document, the term "halogen" means fluorine, chlorine, bromine and / or iodine. Correspondingly, the term "halo" refers to fluoro, chloro, bromo and / or iodo. Within the scope of this document, when an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be monosubstituted, disubstituted or polysubstituted up to full substitution by halogen atoms, for example, "haloC 1-12 Alkyl" and "halogenated C 1-12 Alkoxy" etc.

[0161] The term "C 1- C 12 "Alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C 1- C 10 Alkyl or C 1- C6 alkyl. 1- “C6-alkyl” is understood as meaning preferably a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the radical has 1, 2 or 3 carbon atoms (“C6-alkyl”). 1- C3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0162] The term "C 3- C 12"Cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or polycyclic hydrocarbon ring (also called condensed hydrocarbon ring) having 3-12 carbon atoms. Bicyclic or polycyclic cycloalkyl groups include paracyclic cycloalkyl, bridged cycloalkyl and spirocyclic cycloalkyl; the paracyclic refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spirocyclic refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. For example, the C 3- C 12 The cycloalkyl group may be C 3- C8 monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7- C 12 A cycloalkyl ring, such as a decalin ring.

[0163] The term "C 3- C 12 "Cycloalkenyl" is understood to be an unsaturated monovalent monocyclic, bicyclic hydrocarbon ring or polycyclic hydrocarbon ring (also called condensed hydrocarbon ring) having 3 to 12 carbon atoms and containing 1 to 3 unsaturated double bonds. Preferably, "C 3- C6 cycloalkenyl".

[0164] The term "3-12 membered heterocyclyl" means a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O and S. The heterocyclyl may be attached to the rest of the molecule via any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl, a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl, or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl.

[0165] The term "C 6- C 12"Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6- C 12 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0166] The term "5-12 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. And, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0167] Unless otherwise indicated, a heterocyclyl, heteroaryl, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene.

[0168] The above term “C 1-12 The definition of "alkyl" also applies to 1-12 Other terms for "alkyl", such as the term "halo-C 1-12 Alkyl" or "C 1-12 Alkoxy" or "halogenated C 1-12 Alkoxy" and so on.

[0169] The term "oxa-C 2- C12 "Alkyl" means "C 2- C 12 In the case where 1, 2, 3, 4, 5 or 6 carbon atoms in the "alkyl" are substituted by O.

[0170] The term "thia-C 2- C 12 "Alkyl" means "C 2- C 12 In the case where 1, 2, 3, 4, 5 or 6 carbon atoms in the "alkyl" are substituted by S.

[0171] The term "aza-C 2- C 12 "Alkyl" means "C 2- C 12 In the case where 1, 2, 3, 4, 5 or 6 carbon atoms in the "alkyl" are substituted by NH. BRIEF DESCRIPTION OF THE DRAWINGS

[0172] FIG1 shows the synthetic routes of the hypocrellin derivatives HB-1a, HB-1b, HB-1c, and HB-1d.

[0173] FIG2 shows the hypocrellin derivative HB-33-N in Example 36 of the present invention. + Synthesis route diagram.

[0174] FIG3 shows the hypocrellin derivative HB-57-2N in Example 60 of the present invention. + Synthesis route diagram.

[0175] FIG4 shows the hypocrellin derivative HB-3-4N in Example 6 of the present invention. + The diagram of the interaction with the singlet oxygen scavenger TEMP. HB-3-4N under light conditions + Can effectively generate singlet oxygen.

[0176] FIG5 shows the relationship between HB-1b in Example 3 and the hypocrellin derivative HB-33-N in Example 36 of the present invention. + UV absorption spectrum of HB-33-N (solvent is DMF solution). + The absorption wavelength is significantly red-shifted, and has strong absorption in the phototherapy window.

[0177] FIG6 shows the hypocrellin derivative HB-36-N in Example 39 of the present invention. + HB-36-2N + HB-36-4N + Diagram of the interaction with the singlet oxygen scavenger ABDA. This shows that hypocrellin derivatives can effectively generate singlet oxygen under near-infrared light irradiation.

[0178] FIG. 7 shows the hypocrellin derivative HB-36-N in Example 39 of the present invention. + HB-36-2N + HB-36-4N + The absorbance degradation diagram of ABDA after the reaction with singlet oxygen scavenger ABDA shows that the hypocrellin derivatives can effectively generate singlet oxygen under near-infrared light irradiation. Under the same conditions, HB-36-4N + The most singlet oxygen is produced.

[0179] FIG8 shows HB, the hypocrellin derivative HB-57-N in Example 60 of the present invention. + HB-57-2N + HB-57-4N + Fluorescence imaging of E. coli. This shows that as the number of cations increases, the ability of the derivative to bind to the bacterial membrane becomes stronger.

[0180] Figure 9 shows HB, the hypocrellin derivatives HB-2 and HB-2-N in Example 5 of the present invention. + HB-2-2N + HB-2-4N + The antibacterial effect of plate coating method on Escherichia coli; + HB-2-2N + HB-2-4N + It has excellent anti-negative bacteria effect.

[0181] Figure 10 shows HB, the hypocrellin derivative HB-33-N in Example 36 of the present invention. + HB-33-2N + HB-33-4N + Antibacterial effect of plate coating method on Escherichia coli; Description of HB-33-N + HB-33-2N + HB-33-4N + Has excellent anti-negative bacteria effect, and HB-33-4N + The effect is best.

[0182] FIG. 11 shows the hypocrellin derivative HB-4-N in Example 7 of the present invention. + HB-4-2N + HB-4-4N + The antibacterial effect of plate coating method on Escherichia coli; + HB-4-2N + HB-4-4N + It has excellent anti-negative bacteria effect.

[0183] FIG12 shows HB, the hypocrellin derivative HB-2, HB-2-N in Example 5 of the present invention. + HB-2-2N + HB-2-4N + The concentration-dependent histogram of anti-Escherichia coli activity indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0184] FIG13 shows HB, the hypocrellin derivative HB-6, HB-6-N in Example 9 of the present invention. + HB-6-2N + HB-6-4N + The concentration-dependent histogram of anti-Escherichia coli activity indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0185] Figure 14 shows HB, the hypocrellin derivative HB-9-N in Example 12 of the present invention + HB-9-3N + HB-9-5N + The concentration-dependent histogram of the antibacterial effect on Salmonella typhi indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0186] Figure 15 shows HC, the hypocrellin derivatives HB-11 and HB-11-N in Example 14 of the present invention. + HB-11-2N + HB-11-4N + The concentration-dependent histogram of anti-Escherichia coli activity indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0187] FIG16 shows HA, the hypocrellin derivative HB-19-N in Example 22 of the present invention. + HB-19-2N + HB-19-3N + The concentration-dependent histogram of anti-Escherichia coli activity indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0188] FIG17 shows a bar graph showing the concentration dependence of HA and the hypocrellin derivative HB-23 in Example 25 of the present invention against Proteus, indicating that the hypocrellin derivative has an excellent antibacterial effect.

[0189] FIG18 shows a bar graph showing the concentration dependence of HA and the hypocrellin derivative HB-27 in Example 30 of the present invention against Escherichia coli, indicating that the hypocrellin derivative has an excellent antibacterial effect.

[0190] FIG19 shows a bar graph showing the concentration dependence of the antibacterial activity of HC and the hypocrellin derivative HB-32 in Example 35 of the present invention against Escherichia coli, indicating that the hypocrellin derivative has an excellent antibacterial effect.

[0191] FIG20 shows HC, the hypocrellin derivative HB-33, HB-33-N in Example 36 of the present invention. + HB-33-2N + HB-33-4N + The concentration-dependent histogram of anti-Escherichia coli activity indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0192] Figure 21 shows HA, the hypocrellin derivative HB-36-N in Example 39 of the present invention + HB-36-2N + HB-36-4N + The concentration-dependent histogram of anti-Pseudomonas aeruginosa activity indicates that the hypocrellin derivatives have excellent antibacterial effects.

[0193] FIG22 shows a bar graph showing the concentration dependence of the antibacterial activity of HC and the hypocrellin derivative HB-50 in Example 53 of the present invention against Pseudomonas aeruginosa, indicating that the hypocrellin derivative has an excellent antibacterial effect.

[0194] FIG23 shows HC, the hypocrellin derivative HB-55, HB-55-N in Example 58 of the present invention. + HB-55-2N + HB-55-4N + The concentration-dependent histogram of the antibacterial activity against Pseudomonas aeruginosa indicates that the 14-position cation-substituted hypocrellin derivatives have excellent antibacterial effects.

[0195] FIG24 shows HA, the hypocrellin derivative HB-68, HB-68-N in Example 71 of the present invention. + HB-68-3N + The concentration-dependent histogram of the antibacterial activity against Pseudomonas aeruginosa indicates that the 14-position cation-substituted hypocrellin derivatives have excellent antibacterial effects.

[0196] FIG. 25 shows the hypocrellin derivative HB-33-4N in Example 36 of the present invention. + Antibacterial effect of plate coating method on Candida albicans; Description of HB-33-4N + Has excellent antifungal effect.

[0197] Figure 26 shows HB, the hypocrellin derivative HB-2-4N in Example 5 of the present invention + The concentration-dependent histogram of the anti-cervical cancer cell (HeLa cell) activity indicates that the hypocrellin derivatives have excellent anti-tumor effects.

[0198] FIG27 shows a bar graph showing the concentration dependence of HA and HB against E. coli, indicating that hypocrellin A and hypocrellin B have no antibacterial effect on Gram-negative bacteria E. coli.

[0199] FIG28 shows the polycationically substituted hypocrellin derivative HB-3a-2N in Example 6a of the present invention. + Synthesis route diagram.

[0200] FIG29 shows the polycationically substituted hypocrellin derivative HB-4a-2N in Example 7a of the present invention. + The diagram of the interaction with the singlet oxygen scavenger TEMP. It shows that HB-4a-2N + Can effectively generate singlet oxygen.

[0201] FIG30 shows HB, the polycationically substituted hypocrellin derivative HB-17a-N in Example 20a of the present invention. + HB-17a-2N + HB-17a-3N + Scanning electron microscope image of Escherichia coli after exposure to light; Description of HB-17a-N + HB-17a-2N + HB-17a-3N + It has excellent anti-negative bacteria effect.

[0202] FIG31 shows the antibacterial effect of the polycationically substituted hypocrellin derivative HB-36a in Example 25a of the present invention against Escherichia coli by the plate coating method, indicating that HB-36a has excellent anti-negative bacteria effect.

[0203] FIG32 shows HB, the polycationically substituted hypocrellin derivative HB-2a, HB-2a-N in Example 5a of the present invention. + HB-2a-2N + HB-2a-4N + The concentration-dependent histogram of the antibacterial activity against Escherichia coli indicates that the polycationically substituted hypocrellin derivatives have excellent antibacterial effects.

[0204] FIG33 shows HB, the polycationically substituted hypocrellin derivative HB-6a, HB-6a-N in Example 9a of the present invention. + HB-6a-2N + HB-6a-4N + The concentration-dependent histogram of the antibacterial activity against Escherichia coli indicates that the polycationically substituted hypocrellin derivatives have excellent antibacterial effects.

[0205] Figure 34 shows HC, the polycationic substituted hypocrellin derivative HB-18a-N in Example 21a of the present invention + HB-18a-2N + HB-18a-3N +The concentration-dependent histogram of the antibacterial activity against Pseudomonas aeruginosa indicates that the polycationically substituted hypocrellin derivatives have excellent antibacterial effects.

[0206] Figure 35 shows HC, the polycationic substituted hypocrellin derivative HB-38a-N in Example 27a of the present invention + HB-38a-2N + HB-38a-3N + The concentration-dependent histogram of the antibacterial activity against Escherichia coli indicates that the polycationically substituted hypocrellin derivatives have excellent antibacterial effects. DETAILED DESCRIPTION

[0207] In order to more clearly illustrate the present invention, the present invention is further described below in conjunction with preferred embodiments and drawings. Those skilled in the art should understand that the following specific description is illustrative rather than restrictive and should not be used to limit the scope of protection of the present invention.

[0208] In the present invention, the experimental methods described are conventional methods unless otherwise specified. The raw materials used are all available from public commercial sources unless otherwise specified. The percentages described are by mass unless otherwise specified. The M described is mol / L unless otherwise specified.

[0209] The method for testing the minimum inhibitory concentration (MBC) of anti-negative bacteria-Escherichia coli in this application is:

[0210] The minimum inhibitory concentration of the derivatives was evaluated using the plate spreading method using Escherichia coli as an example.

[0211] (1) Bacterial culture: Pick a single colony of Escherichia coli in 50 mL LB medium and culture at 37°C and 220 rpm for 18-24 h. Measure OD600 = 1 (default 2x10 9 CFU mL -1 );

[0212] (2) Add photosensitizer: dilute with saline or PBS to the desired concentration (1x10 5 CFU mL -1 For example, different concentrations of photosensitizing drugs were added to 1 mL of bacterial suspension, and the mixture was incubated at 37°C for 2 h.

[0213] (3) Illumination: For the illumination group, a 532 nm or 635 nm laser (100 mW cm) was used during the culture period. -2 ) Continuous irradiation for 15 minutes.

[0214] (4) Plate spreading: Bacteria were collected by centrifugation (8000 rpm, 5 min), diluted 100-fold with saline, and 100 μL of the E. coli suspension was evenly spread on LB agar plates and cultured at 37°C for 12-16 h until colonies formed.

[0215] (5) Counting: The bacterial survival rate was calculated by comparing the colony counts in the sample treatment group with those in the saline control group.

[0216] The test method for the minimum inhibitory concentration of several other bacterial species (Pseudomonas aeruginosa, Proteus, Salmonella typhi, Bordetella pertussis, Salmonella, Klebsiella, Neisseria meningitidis, Staphylococcus aureus) is basically the same as that for the negative bacteria - Escherichia coli.

[0217] The method for testing the generation of reactive oxygen species in this application is:

[0218] (1) ESR test method, using TEMP as the capture agent:

[0219] Add 10 μL of singlet oxygen capture probe TEMP to 100 μL of HB-3-4N + (1 mM) solution, and the mixture was placed in a 0.1 W cm - 2 , 532nm laser irradiation. The changes in the signal peak were recorded using an electron paramagnetic resonance spectrometer. The test results are shown in Figure 3.

[0220] (2) Chemical capture method, using ABDA as the capture agent:

[0221] HB-36-N + HB-36-2N + and HB-36-4N + The absorption of the aqueous solution at 635 nm was diluted to 0.2. 20 μL, 1 mg mL - 2 Add the ABDA solution of the above dilution solution. Place the mixed solution in 0.01W cm -2 The sample was irradiated with a 635nm laser. The absorption of ABDA was recorded every 30 seconds. The test results are shown in Figures 5 and 6.

[0222] The test method for bacterial imaging in this application is:

[0223] After centrifugation of E. coli culture, the supernatant was discarded, washed three times with physiological saline and diluted to 10 8 CFU mL -1 . Respectively with HB, HB-2-N + HB-2-2N + HB-2-4N +After 3-9 hours of co-incubation, centrifuge and discard the supernatant, wash three times with physiological saline until no obvious color is found, redisperse in physiological saline, drop into a confocal dish (or slide), and photograph using a laser confocal microscope.

[0224] The cytotoxicity test method in this application is the MTT method (anti-tumor effect test, cell half-inhibitory concentration IC 50 ):

[0225] A certain concentration of HeLa cells were seeded in a 96-well plate and cultured at 5% CO2 and 37°C for 24 hours. Then, different concentrations of the test substances (HB or HB-2-4N + ) solution was added to the 96-well plate and incubated for 2 h. Then 0.1 W cm -2 The cells were irradiated with a 532 nm laser at a power of 10 min. Then, the prepared MTT aqueous solution (20 μL, 5 mg mL -1 After 4 hours of incubation, the solution was removed to dissolve the purple crystals formed by MTT and intracellular succinase. The absorbance at 570 nm in the 96-well plate was measured using a microplate reader. A concentration of 0 μM was used as a reference, and the survival rate was considered to be 100%. Cell survival rates were calculated at different concentrations. Each experiment was repeated 6 times in parallel, and the average value was calculated.

[0226] The half-inhibitory concentration IC of several other cell lines (esophageal cancer cells, bile duct cancer cells, skin squamous cell carcinoma cells) 50 The testing method is basically the same as that for HeLa cells.

[0227] The solvent used for the UV absorption and fluorescence spectra measured in all the examples in this application is N,N-dimethylformamide (DMF).

[0228] As is well known to those skilled in the art, hypocrellin exists in isomers. Therefore, the double bond between positions 13, 14, and 15 in the structure given in the following examples can exist between positions 13 and 14, or between positions 14 and 15, and the two expressions represent the same structure.

[0229] The salts prepared in the following examples all contain anionic counterions. Although the specific ion types are not shown, those skilled in the art can infer the specific anionic types based on the raw materials used to prepare the salts.

[0230] Example 1

[0231] Extraction of Hypocrellin A (HA): HA is extracted from the natural product Hypocrellin. The preparation method is based on the literature reference (Organic Chemistry, 1989, 9, 252-254), and has been appropriately improved. Weigh 100g of Hypocrellin A, pulverize it with a pulverizer, place it in a 2000mL two-necked flask, reflux it for 2h with 1000mL acetone as a solvent, extract 4-5 times until the extract is nearly colorless, remove a small amount of solid insoluble matter that infiltrates in the extract by filtering, then remove acetone by rotary evaporator, dissolve it with 500mL dichloromethane, wash with 4×400mL distilled water, separate the organic layer and spin-dry, wash the solid residue with 5×100mL petroleum ether, and let it dry naturally in air. Then recrystallize it twice with chloroform-petroleum ether. The resulting crystals are the target product Hypocrellin A (HA), with a purity of more than 98%. High-purity hypocrellin A can be further purified by thin-layer silica gel chromatography using petroleum ether:ethyl acetate:anhydrous ethanol (V=30:10:1) as a developing solvent.

[0232] Preparation of Hypocrellin B (HB): HB is obtained by dehydrating HA in an alkaline aqueous solution. The preparation method is based on the literature (Organic Chemistry, 1989, 9, 252-254), with appropriate modifications. The specific method is as follows: 1 g of HA is dissolved in 1000 mL of a 1.5% aqueous KOH solution. After stirring in the dark for 24 hours, the mixture is neutralized with a slight excess of dilute hydrochloric acid and filtered to obtain 0.98 g of hypocrellin B, with a yield of 98%.

[0233] Preparation of deacetylhypocrellin (HC): 200 mg of HB was dissolved in 100 mL of 1.5% potassium hydroxide aqueous solution and refluxed in the dark for 8 h. After cooling, the mixture was neutralized with a slightly excess of dilute hydrochloric acid. The product was extracted with dichloromethane and separated and purified to obtain 110 mg of HC with a yield of 56%.

[0234] Example 2

[0235] The cationic derivatives used in the present invention are prepared by the following general method, which is described using S2 as an example:

[0236] Preparation of Intermediate S1: 1,6-Dibromohexane (20 ml, 0.12 mol) and pyridine (2.0 ml, 0.03 mol) were reacted in tetrahydrofuran at room temperature for 24 h. The crude product was washed three times with ethyl acetate (3 x 50 ml) to remove unreacted reactants and dried under vacuum to yield 8.43 g of S1 as a white powder. 1H NMR (400MHz, D2O): δ8.89-8.83(t,2H),8.56(t,1H),8.08(d,2H),4.64(t,2H),3.50(t,2H),2.06(p,2H),1.86(p,2H),1.50(p,2H),1.38(p,2H). MS(ESI + ): C 11 H 17 BrN + (M / Z)243.26.

[0237] Preparation of Intermediate S2: Intermediate S1 (2 g, 6.6 mmol) and N,N,N',N'-tetramethyl-1,6-hexanediamine (15 ml, 0.07 mol) were reacted in a mixture of acetonitrile and dimethyl sulfoxide (V = 3:1) at 45°C for 36 h. The mixture was poured into excess diethyl ether, washed and filtered, and dried under vacuum at room temperature for 24 h to yield 2.13 g of the product S2 as a light yellow solid. 1 H NMR (400MHz, D2O): δ8.88(t,2H),8.59(t,1H),8.12(d,2H),4.66(t,2H),3.28(t,4H),3.07(s,6 H),2.46(t,2H),2.29(s,6H),2.09(t,2H),1.78(t,4H),1.55(p,2H),1.46(p,4H),1.40(p,4H). MS(ESI + ): C 21 H 41 N3 2+ (M / Z)168.16.

[0238] In addition, cationic derivatives were prepared by referring to the method of S2 Br - , n is the number of quaternary ammonium salt units, n = 2, 4.

[0239] In addition, cationic derivatives were prepared by referring to the method of S2 Br - , n is the number of quaternary ammonium salt units, n = 1, 2, 4.

[0240] Example 3

[0241] The cationic derivatives used in the present invention are prepared by the following general method, which is described using S5 as an example:

[0242] Preparation of intermediate S3: 1,6-dibromohexane (20 mL, 0.12 mol) and triethylamine (4.2 mL, 0.03 mol) were reacted in tetrahydrofuran at room temperature for 24 h. The crude product was washed three times with ethyl acetate (3 × 50 mL) to remove unreacted reactants and dried under vacuum to obtain 9.21 g of white solid S3. MS (ESI + ): C 12 H 27 BrN + (M / Z) 265.25.

[0243] Preparation of intermediate S4: Intermediate S3 (2.0 g, 0.006 mol) and 1,4-diazabicyclo[2.2.2]octane (1.1 g, 0.01 mol) were reacted in a mixed solvent of acetonitrile:dimethyl sulfoxide (V=3:1) at 45°C for 24 h. The mixture was poured into excess ether, washed and filtered, and dried under vacuum at room temperature for 24 h to obtain 1.89 g of white solid product S4. MS (ESI + ): C 24 H 51 BrN3 3+ (M / Z)148.65.

[0244] Preparation of intermediate S5: Intermediate S4 (2.7 g, 0.006 mol) and 1,6-dibromohexane (2 mL, 0.012 mol) were reacted in a mixed solvent of acetonitrile:dimethyl sulfoxide (V=3:1) at 65°C for 48 h. The mixture was poured into excess ether, washed and filtered, and dried under vacuum at room temperature for 24 h to obtain 2.19 g of the product S5 as a light yellow solid. MS (ESI + ): C 18 H 39 BrN3 3+ (M / Z)153.44.

[0245] Example 4

[0246] The preparation methods of compound HB-1a (HC substituted with an aldehyde group at the 14th position), compound HB-1a' (HB substituted with an aldehyde group at the 14th position), compound HB-1b (HC substituted with a hydroxymethyl group at the 14th position), compound HB-1b' (HB substituted with a hydroxymethyl group at the 14th position), compound HB-1c (HC substituted with a carboxyl group at the 14th position), compound HB-1c' (HB substituted with a carboxyl group at the 14th position), compound HB-1d (HC substituted with a bromomethyl group at the 14th position), and compound HB-1d' (HB substituted with a bromomethyl group at the 14th position) were prepared according to the literature (Organic Chemistry, 1990, 10, 339-342), with appropriate improvements. Their structures are shown below:

[0247] Preparation of HB-1a (HB-1a'): 100 mg of HC (HB is used as the starting material in the preparation of HB-1a'), 200 mg of selenium dioxide, and 10 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 6 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, and the mixture was extracted three times with 100 mL of dichloromethane. The organic layer was dried using a rotary evaporator to obtain a red solid. After separation and purification, 98 mg of HB-1a was obtained.

[0248] Preparation of HB-1b (HB-1b'): 100 mg of HC (HB is used as the starting material in the preparation of HB-1b'), 50 mg of selenium dioxide, and 20 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 3 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic layer was dried using a rotary evaporator to obtain a red solid. After separation and purification, 87 mg of HB-1b and 10 mg of HB-1a were obtained.

[0249] Preparation of HB-1c (HB-1c'): 100 mg of HC (HB is used as the starting material in the preparation of HB-1c'), 100 mg of selenium dioxide, and 10 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 12 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, and the mixture was extracted three times with 100 mL of dichloromethane. The organic layer was dried using a rotary evaporator to obtain a red solid. After separation and purification, 61 mg of HB-1c was obtained.

[0250] Preparation of HB-1d (HB-1d'): Dissolve 100 mg of HB-1b (HB-1b' is used as a raw material in the preparation of HB-1d') and 100 mg of carbon tetrabromide in anhydrous dichloromethane. Stir at room temperature for 3 h in anhydrous and oxygen-free conditions. The organic layer is dried on a rotary evaporator to obtain a red solid, which is separated and purified to obtain 82 mg of HB-1d.

[0251] Example 4

[0252] The preparation method for the raw material compound HB-1-NN, which forms a nitrogen-containing heterocycle at the 2- and 3-positions of hypocrellin, described in the following examples, was based on the literature (Biomaterials, 2018, 185, 133-141), with appropriate modifications. The preparation process for HB-1-NN is as follows: HC and ethylenediamine are dissolved in anhydrous tetrahydrofuran and heated to 55°C. Stir under nitrogen in the dark for 10 hours. After removing the solvent under reduced pressure, the mixture is extracted with dichloromethane, dried, and spin-dried to dryness. The remaining crude product is separated by column chromatography to yield compound HB-1-NN.

[0253] Preparation of HB-1-NN-b: 100 mg of HB-1-NN, 50 mg of selenium dioxide, and 20 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 3 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, which was extracted three times with dichloromethane. The organic layer was dried using a rotary evaporator to obtain a black solid. After separation and purification, 58 mg of HB-1-NN-b was obtained.

[0254] Preparation method of HB-1-NN-d: Dissolve 100 mg of HB-1-NN-b and 100 mg of carbon tetrabromide in anhydrous dichloromethane, stir at room temperature for 2.5 hours under anhydrous and oxygen-free conditions, and dry the organic layer using a rotary evaporator to obtain a black solid. After separation and purification, 75 mg of HB-1-NN-d is obtained.

[0255] The preparation process of other nitrogen-containing heterocyclic raw material compounds formed at the 2- and 3-positions of hypocrellin is basically based on the preparation method of HB-1-NN-d.

[0256] Example 4

[0257] The preparation method of the raw material compound HB-1-NS in which the 4 and 5 positions of the hypocrellin form a heterocyclic ring is referred to in the following examples (J. Mater. Chem. B, 2022, 10, 57-63, ACS Appl. Bio Mater. 2020, 3, 3817-3826), and appropriate improvements have been made. The preparation process of the compound HB-1-NS is as follows: HC and mercaptoethylamine hydrochloride are dissolved in DMSO solution, and 36% ammonia water is used to adjust the pH of the solution to 9-10, and the solution is stirred in the dark at room temperature for 12 hours. After the reaction, the pH value is adjusted to neutral with dilute hydrochloric acid, followed by multiple extractions with CH2Cl2 and water, and the solvent is removed by distillation under reduced pressure. The crude product is separated and purified by thin layer chromatography and column chromatography to obtain compound HB-1-NS.

[0258] Preparation of HB-1-NS-b: 100 mg of HB-1-NS, 50 mg of selenium dioxide, and 15 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 2.5 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, which was extracted three times with dichloromethane. The organic layer was dried using a rotary evaporator to obtain a black solid. After separation and purification, 65 mg of HB-1-NS-b was obtained.

[0259] Preparation method of HB-1-NS-d: Dissolve 100 mg of HB-1-NS-b and 100 mg of carbon tetrabromide in anhydrous dichloromethane, stir at room temperature for 2.5 hours under anhydrous and oxygen-free conditions, and dry the organic layer using a rotary evaporator to obtain a black solid. After separation and purification, 78 mg of HB-1-NS-d is obtained.

[0260] The preparation process of other raw material compounds in which the 4- and 5-positions of hypocrellin form heterocyclic rings is basically based on the preparation method of HB-1-NS-d.

[0261] Example 5

[0262] The acetonitrile solution containing 100 mg of HB-1d was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain red solid products HB-2 and HB-2-N, respectively. + HB-2-2N + HB-2-4N + HB-2: yield 72.6%; MS (ESI + ): C 41 H 44 N2O8 2+ (M / Z) 346.15; UV maximum absorption wavelength: 465nm, 554nm; fluorescence maximum emission wavelength: 612nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 1.55μM; HeLa cell half inhibitory concentration (IC 50 ):135nM. HB-2-N + : Yield: 68.4%; MS (ESI + ): C 49 H 62 N3O8 3+ (M / Z) 273.48; UV maximum absorption wavelength: 468nm, 556nm; fluorescence maximum emission wavelength: 625nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.55μM; HeLa cell half inhibitory concentration (IC 50 ):128nM. HB-2-2N + : Yield: 60.0%; MS (ESI + ): C 57 H 80 N4O8 4+ (M / Z) 237.14; UV maximum absorption wavelength: 472nm, 559nm; fluorescence maximum emission wavelength: 651nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.35μM; HeLa cell half inhibitory concentration (IC 50 ):113nM. HB-2-4N +: Yield: 46.0%; MS (ESI + ): C 73 H 116 N6O8 6+ (M / Z) 200.81; UV maximum absorption wavelength: 485nm, 565nm; fluorescence maximum emission wavelength: 671nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.1μM; HeLa cell half inhibitory concentration (IC 50 ): 98nM.

[0263] Example 6

[0264] The acetonitrile solution containing 100 mg of HB-1d was added dropwise to 270 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 2:1), heated to 57 ° C under nitrogen protection, and stirred in the dark for 50 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain red solid products HB-3 and HB-3-N, respectively. + HB-3-2N + HB-3-4N + HB-3: yield 82.2%; MS (ESI + ): C 36 H 40 NO8 + (M / Z) 614.27; UV maximum absorption wavelength: 466nm, 557nm; fluorescence maximum emission wavelength: 610nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 2.0μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ):156nM. HB-3-N + : Yield: 71.4%; MS (ESI + ): C 44 H 58 N2O8 2+ (M / Z) 371.20; UV maximum absorption wavelength: 462nm, 539nm; fluorescence maximum emission wavelength: 615nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.5μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431) 50 ):120nM. HB-3-2N + : Yield: 60.0%; MS (ESI + ): C 52 H 76 N3O83+ (M / Z) 290.18; UV maximum absorption wavelength: 470nm, 558nm; fluorescence maximum emission wavelength: 650nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431) 50 ):102nM. HB-3-4N + : Yield: 46.0%; MS (ESI + ): C 68 H 112 N5O8 5+ (M / Z) 225.36; UV maximum absorption wavelength: 486nm, 566nm; fluorescence maximum emission wavelength: 675nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431) 50 ): 97nM.

[0265] Example 7

[0266] The acetonitrile solution containing 100 mg of HB-1d was added dropwise to 330 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 50 ° C under nitrogen protection, and stirred in the dark for 38 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain red solid products HB-4-N + HB-4-2N + HB-4-4N + HB-4-N + : Yield: 71.5%; MS (ESI + ): C 39 H 48 N2O8 2+ (M / Z) 336.17; UV maximum absorption wavelength: 471nm, 546nm; fluorescence maximum emission wavelength: 1.55μM. Minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 1.60μM; HeLa cell half inhibitory concentration (IC 50 ):131nM. HB-4-2N + : Yield: 58.7%; MS (ESI + ): C 46 H 64 N3O8 3+(M / Z) 262.15; UV maximum absorption wavelength: 482nm, 556nm; fluorescence maximum emission wavelength: 641nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.55μM; HeLa cell half inhibitory concentration (IC 50 ):108nM. HB-4-4N + : Yield: 38.0%; MS (ESI + ): C 63 H 102 N5O8 5+ (M / Z) 211.35; UV maximum absorption wavelength: 489nm, 568nm; fluorescence maximum emission wavelength: 678nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.15μM; HeLa cell half inhibitory concentration (IC 50 ): 101nM.

[0267] Example 8

[0268] The acetonitrile solution containing 100 mg of HB-1d' was added dropwise to 350 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 2.5:1), heated to 50 ° C under nitrogen protection, and stirred in the dark for 45 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain red solid products HB-5-N + HB-5-2N + HB-5-4N + HB-5-N + : Yield: 61.7%; MS (ESI + ): C 43 H 54 NO9P 2+ (M / Z) 379.67; UV maximum absorption wavelength: 476nm, 548nm; fluorescence maximum emission wavelength: 610nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.50μM. HB-5-2N + : Yield: 48.5%; MS (ESI + ): C 53 H 76 NO9P2 3+ (M / Z) 310.83; UV maximum absorption wavelength: 480nm, 558nm; fluorescence maximum emission wavelength: 646nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-5-4N +: Yield: 38.5%; MS (ESI + ): C 73 H 120 NO9P4 5+ (M / Z) 255.75; UV maximum absorption wavelength: 487nm, 567nm; fluorescence maximum emission wavelength: 676nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.2μM.

[0269] Example 9

[0270] The acetonitrile solution containing 100 mg of HB-1d' was added dropwise to 350 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain red solid products HB-6 and HB-6-N, respectively. + HB-6-2N + HB-6-4N + HB-6: yield 73.4%; MS (ESI + ): C 42 H 49 N3O9 2+ (M / Z) 369.67; UV maximum absorption wavelength: 466nm, 555nm; fluorescence maximum emission wavelength: 615nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-6-N + : Yield: 66.5%; MS (ESI + ): C 50 H 67 N4O9 3+ (M / Z) 289.16; UV maximum absorption wavelength: 469nm, 558nm; fluorescence maximum emission wavelength: 626nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-6-2N + : Yield: 63.0%; MS (ESI + ): C 58 H 85 N5O9 4+ (M / Z) 248.90; UV maximum absorption wavelength: 473nm, 558nm; fluorescence maximum emission wavelength: 648nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-6-4N +: Yield: 45.8%; MS (ESI + ): C 74 H 121 N7O9 6+ (M / Z) 208.65; UV maximum absorption wavelength: 483nm, 563nm; fluorescence maximum emission wavelength: 670nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM.

[0271] Example 10

[0272] 100mg of HB-1b, 150mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 3, 5), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 24 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-7-N + HB-7-3N + HB-7-5N + HB-7-N + : Yield: 86.9%; MS (ESI + ): C 41 H 48 NO 10 + (M / Z) 714.32; UV maximum absorption wavelength: 472nm, 563nm; fluorescence maximum emission wavelength: 635nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 1.95μM. HB-7-3N + : Yield: 83.0%; MS (ESI + ): C 61 H 92 N3O 10 3+ (M / Z) 342.22; UV maximum absorption wavelength: 475nm, 556nm; fluorescence maximum emission wavelength: 649nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.50μM. HB-7-5N + : Yield: 85.6%; MS (ESI + ): C 81 H 136 N5O 10 5+(M / Z) 267.80; UV maximum absorption wavelength: 486nm, 575nm; fluorescence maximum emission wavelength: 681nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.20μM.

[0273] Example 11

[0274] Containing 100mg HB-1b, 350mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 24 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-8 and HB-8-N, respectively. + HB-8-2N + HB-8-4N + HB-8: Yield: 89.2%; MS (ESI + ): C 38 H 34 NO 10 + (M / Z) 664.21; UV maximum absorption wavelength: 468nm, 556nm; fluorescence maximum emission wavelength: 613nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.95μM. HB-8-N + : Yield: 85.8%; MS (ESI + ): C 52 H 64 N2O 10 2+ (M / Z) 438.22; UV maximum absorption wavelength: 470nm, 560nm; fluorescence maximum emission wavelength: 633nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-8-2N + : Yield: 83.6%; MS (ESI + ): C 66 H 94 N3O 10 3+ (M / Z) 362.89; UV maximum absorption wavelength: 476nm, 558nm; fluorescence maximum emission wavelength: 648nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-8-4N + : Yield: 75.7%; MS (ESI + ): C 94 H154 N5O 10 5+ (M / Z) 302.83; UV maximum absorption wavelength: 486nm, 569nm; fluorescence maximum emission wavelength: 677nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM.

[0275] Example 12

[0276] Containing 100mg HB-1c, 200mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 3, 5), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 28 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-9-N + HB-9-3N + HB-9-5N + HB-9-N + : Yield: 87.3%; MS (ESI + ): C 38 H 42 NO 10 + (M / Z) 672.28; UV maximum absorption wavelength: 466nm, 555nm; fluorescence maximum emission wavelength: 612nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 2.0μM. HB-9-3N + : Yield: 86.7%; MS (ESI + ): C 48 H 66 N3O 10 3+ (M / Z) 281.49; UV maximum absorption wavelength: 470nm, 561nm; fluorescence maximum emission wavelength: 632nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 0.55μM. HB-9-5N + : Yield: 79.6%; MS (ESI + ): C 58 H 90 N5O 10 5+ (M / Z) 203.33; UV maximum absorption wavelength: 477nm, 559nm; fluorescence maximum emission wavelength: 649nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 0.15μM.

[0277] Example 13

[0278] Containing 100mg HB-1-NH2, 350mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4), 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 48 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-10-N + HB-10-2N + HB-10-4N + HB-10-N + : Yield: 86.5%; MS (ESI + ): C 69 H 103 N2O9 + (M / Z) 1103.76; UV maximum absorption wavelength: 468nm, 558nm; fluorescence maximum emission wavelength: 615nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.95μM. HB-10-2N + : Yield: 82.1%; MS (ESI + ): C 103 H 173 N3O9 2+ (M / Z) 798.65; UV maximum absorption wavelength: 472nm, 562nm; fluorescence maximum emission wavelength: 635nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.50μM. HB-10-4N + : Yield: 78.3%; MS (ESI + ): C 171 H 313 N5O9 4+ (M / Z) 645.60; UV maximum absorption wavelength: 476nm, 565nm; fluorescence maximum emission wavelength: 651nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40μM.

[0279] Example 14

[0280] The acetonitrile solution containing 100 mg of HB-1d was added dropwise to 280 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 54 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain red solid products HB-11 and HB-11-N, respectively. + HB-11-2N + HB-11-4N + HB-11: Yield: 68.2%; MS (ESI + ): C 41 H 44 N2O8 2+ (M / Z) 346.15; UV maximum absorption wavelength: 468nm, 558nm; fluorescence maximum emission wavelength: 617nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM; half inhibitory concentration (IC) of esophageal cancer cells (KYSE-150) 50 ):136nM. HB-11-N + : Yield: 56.5%; MS (ESI + ): C 53 H 68 N4O8 4+ (M / Z) 222.12; UV maximum absorption wavelength: 470nm, 561nm; fluorescence maximum emission wavelength: 632nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM; half inhibitory concentration (IC 50 ):118nM. HB-11-2N + : Yield: 52.1%; MS (ESI + ): C 65 H 92 N6O8 6+ (M / Z) 180.78; UV maximum absorption wavelength: 475nm, 556nm; fluorescence maximum emission wavelength: 646nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.05μM; half inhibitory concentration (IC) for esophageal cancer cells (KYSE-150) 50 ):102nM. HB-11-4N + : Yield: 35.8%; MS (ESI + ): C 89 H 140 N 10 O8 10+(M / Z) 147.70; UV maximum absorption wavelength: 482nm, 561nm; fluorescence maximum emission wavelength: 675nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.01μM; half inhibitory concentration (IC 50 ): 97nM.

[0281] Example 15

[0282] The acetonitrile solution containing 100 mg of HB-1d' was added dropwise to 270 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 54 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain red solid products HB-12-N + HB-12-2N + HB-12-4N + HB-12-N + : Yield: 62.4%; MS (ESI + ): C 45 H 56 N3O 10 3+ (M / Z) 266.13; UV maximum absorption wavelength: 467nm, 557nm; fluorescence maximum emission wavelength: 618nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.60μM. HB-12-2N + : Yield: 51.0%; MS (ESI + ): C 55 H 76 N5O 10 5+ (M / Z) 193.31; UV maximum absorption wavelength: 471nm, 562nm; fluorescence maximum emission wavelength: 621nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20μM. HB-12-4N + : Yield: 46.2%; MS (ESI + ): C 75 H 116 N9O 10 9+ (M / Z) 144.76; UV maximum absorption wavelength: 476nm, 557nm; fluorescence maximum emission wavelength: 645nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM.

[0283] Example 16

[0284] Dissolve 100 mg HB-1b' and 62.1 mg trichloroacetonitrile in anhydrous dichloromethane, add 3 drops of BUN (urea nitrogen) under ice bath, and react for 10 minutes. Separate by column chromatography to obtain the trichloroacetonitrile derivative of HB-1b. n is the number of quaternary ammonium salt units, n = 1, 2, 4) and the derivative were dissolved in acetonitrile solution, 5 drops of TMSOTF were added dropwise under nitrogen protection at -40 ° C, and the reaction was stirred in the dark for 0.5 hours. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The obtained crude product was further separated by silica gel plate chromatography to obtain red solid products HB-13-N + HB-13-2N + HB-13-4N + HB-13-N + : Yield: 52.4%; MS (ESI + ): C 42 H 46 N2O 12 2+ (M / Z) 385.15; UV maximum absorption wavelength: 466nm, 555nm; fluorescence maximum emission wavelength: 617nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 1.55μM. HB-13-2N + : Yield: 43.0%; MS (ESI + ): C 50 H 62 N4O 12 4+ (M / Z) 227.60; UV maximum absorption wavelength: 470nm, 560nm; fluorescence maximum emission wavelength: 622nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.40μM. HB-13-4N + : Yield: 36.1%; MS (ESI + ): C 66 H 94 N8O 12 8+ (M / Z) 148.83; UV maximum absorption wavelength: 478nm, 558nm; fluorescence maximum emission wavelength: 646nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.05μM.

[0285] Example 17

[0286] Dissolve 100 mg HB-1b' and 62.1 mg trichloroacetonitrile in anhydrous dichloromethane, add 3 drops of BUN under ice bath, and react for 10 minutes. Separate by column chromatography to obtain the trichloroacetonitrile derivative of HB-1b. n is the number of quaternary ammonium salt units, n = 1, 2, 4) and the derivative were dissolved in acetonitrile solution, 5 drops of TMSOTF (trimethylsilyl trifluoromethanesulfonate) were added dropwise under nitrogen protection at -40 ° C, and the reaction was stirred in the dark for 0.5 h. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The obtained crude product was further separated by silica gel plate chromatography to obtain red solid products HB-14-N + HB-14-2N + HB-14-4N + HB-14-N + : Yield: 48.5%; MS (ESI + ): C 67 H 76 N2O9PS 3+ (M / Z) 371.83; UV maximum absorption wavelength: 474nm, 561nm; fluorescence maximum emission wavelength: 625nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-14-2N + : Yield: 35.0%; MS (ESI + ): C 83 H 108 N4O9PS 5+ (M / Z) 273.55; UV maximum absorption wavelength: 478nm, 565nm; fluorescence maximum emission wavelength: 629nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20μM. HB-14-4N + : Yield: 25.3%; MS (ESI + ): C 115 H 172 N8O9PS 9+ (M / Z) 208.14; UV maximum absorption wavelength: 482nm, 568nm; fluorescence maximum emission wavelength: 645nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM.

[0287] Example 18

[0288] 100mg HB-1a, 360mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 3) was added to the dimethyl sulfoxide solution, mixed thoroughly, and refluxed in the dark under nitrogen protection for 10 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain the crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-15 and HB-15-N, respectively. + HB-15-2N + HB-15-3N + HB-15: yield 51.2%; MS (ESI + ): C 34 H 35 N2O8 + (M / Z) 599.23; UV maximum absorption wavelength: 475nm, 565nm; fluorescence maximum emission wavelength: 625nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 2.0μM. HB-15-N + : Yield: 42.2%; MS (ESI + ): C 44 H 55 N4O8 3+ (M / Z) 255.80; UV maximum absorption wavelength: 481nm, 569nm; fluorescence maximum emission wavelength: 635nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-15-2N + : Yield: 33.5%; MS (ESI + ): C 54 H 75 N6O8 5+ (M / Z) 187.11; UV maximum absorption wavelength: 486nm, 572nm; fluorescence maximum emission wavelength: 645nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM. HB-15-3N + : Yield: 25.3%; MS (ESI + ): C 64 H 95 N8O8 7+ (M / Z) 157.67; UV maximum absorption wavelength: 496nm, 579nm; fluorescence maximum emission wavelength: 667nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM.

[0289] Example 19

[0290] 100 mg HB-1a', 330 mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 3) was dissolved in dimethyl sulfoxide solution, mixed thoroughly, and refluxed in the dark under nitrogen protection for 10 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-16-N + HB-16-2N + 、HB-16-4N + HB-16-N + : Yield: 56.3%; MS (ESI + ): C 44 H 51 N3O 12 S 2+ (M / Z) 422.65; UV maximum absorption wavelength: 473nm, 562nm; fluorescence maximum emission wavelength: 623nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.60μM. HB-16-2N + : Yield: 37.9%; MS (ESI + ): C 55 H 73 N5O 12 S 4+ (M / Z) 256.87; UV maximum absorption wavelength: 480nm, 568nm; fluorescence maximum emission wavelength: 635nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40μM. HB-16-4N + : Yield: 28.5%; MS (ESI + ): C 66 H 95 N7O 12 S 6+ (M / Z) 201.61; UV maximum absorption wavelength: 485nm, 573nm; fluorescence maximum emission wavelength: 645nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM.

[0291] Example 20

[0292] 100 mg HB-1b', 340 mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 32 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-17-N +HB-17-2N + HB-17-4N + HB-17-N + : Yield: 87.3%; MS (ESI + ): C 57 H 68 N3O 12 3+ (M / Z) 328.82; UV maximum absorption wavelength: 466nm, 554nm; fluorescence maximum emission wavelength: 615nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella: 0.55μM. HB-17-2N + : Yield: 81.2%; MS (ESI + ): C 71 H 96 N5O 13 5+ (M / Z) 245.33; UV maximum absorption wavelength: 471nm, 562nm; fluorescence maximum emission wavelength: 633nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella: 0.20μM. HB-17-4N + : Yield: 78.1%; MS (ESI + ): C 99 H 152 N9O 13 9+ (M / Z) 186.23; UV maximum absorption wavelength: 474nm, 559nm; fluorescence maximum emission wavelength: 649nm; minimum inhibitory concentration (MBC) for negative bacteria - Salmonella: 0.05μM.

[0293] Example 21

[0294] 100mg HB-1b, 380mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 32 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-18-N + HB-18-2N + HB-18-3N + HB-18-N + : Yield: 82.1%; MS (ESI + ): C 54 H 66 N3O10 3+ (M / Z) 305.49; UV maximum absorption wavelength: 465nm, 555nm; fluorescence maximum emission wavelength: 615nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1): 50 ):136nM. HB-18-2N + : Yield: 79.2%; MS (ESI + ): C 68 H 94 N5O 10 5+ (M / Z) 228.13; UV maximum absorption wavelength: 472nm, 564nm; fluorescence maximum emission wavelength: 635nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1) 50 ):109nM. HB-18-3N + : Yield: 76.1%; MS (ESI + ): C 82 H 122 N7O 10 7+ (M / Z) 194.98; UV maximum absorption wavelength: 476nm, 558nm; fluorescence maximum emission wavelength: 651nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1) 50 ):89nM.

[0295] Example 22

[0296] 100 mg HB-1-NH2', 310 mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 3), 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-19-N + HB-19-2N + HB-19-3N + HB-19-N + : Yield: 73.6%; MS (ESI + ): C 51 H 65 N3O13 2+ (M / Z) 463.72; UV maximum absorption wavelength: 465nm, 560nm; fluorescence maximum emission wavelength: 620nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-19-2N + : Yield: 68.5%; MS (ESI + ): C 65 H 95 N5O 13 4+ (M / Z) 288.42; UV maximum absorption wavelength: 475nm, 566nm; fluorescence maximum emission wavelength: 636nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40μM. HB-19-3N + : Yield: 50.4%; MS (ESI + ): C 78 H 121 N7O 13 6+ (M / Z) 227.31; UV maximum absorption wavelength: 477nm, 558nm; fluorescence maximum emission wavelength: 656nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM.

[0297] Example 23

[0298] 100 mg HB-1-NH2, 380 mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-20-N + HB-20-2N + HB-20-N + : Yield: 71.0%; MS (ESI + ): C 54 H 71 N3O 14 2+ (M / Z) 492.74; UV maximum absorption wavelength: 462nm, 561nm; fluorescence maximum emission wavelength: 621nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 1.50μM. HB-20-2N + : Yield: 63.2%; MS (ESI + ): C63 H 89 N5O 14 4+ (M / Z) 284.90; UV maximum absorption wavelength: 474nm, 567nm; fluorescence maximum emission wavelength: 635nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 0.40μM.

[0299] Example 24

[0300] The acetonitrile solution containing 100 mg of HB-1d' was added dropwise to 350 mg of the cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 52 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-21. HB-21: Yield 75.2%; MS (ESI + ): C 55 H 78 N4O 10 4+ (M / Z) 238.64; UV maximum absorption wavelength: 471nm, 561nm; fluorescence maximum emission wavelength: 627nm; minimum inhibitory concentration (MBC) against negative bacteria - Klebsiella: 0.35μM; HeLa cell half inhibitory concentration (IC 50 ):182nM.

[0301] Example 25

[0302] The acetonitrile solution containing 100 mg of HB-1d was added dropwise to 385 mg of the cationic derivative ( ) in a mixture of acetonitrile and dimethyl sulfoxide (V=3:1), heated to 55°C under nitrogen, and stirred in the dark for 56 hours. After completion, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-22. HB-22: Yield 69.2%; MS (ESI + ): C 61 H 86 N5O8 5+ (M / Z) 203.32; UV maximum absorption wavelength: 475nm, 565nm; fluorescence maximum emission wavelength: 628nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.15μM.

[0303] Example 26

[0304] The acetonitrile solution containing 100 mg of HB-1d was added dropwise to 360 mg of the cationic derivative ( A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 56 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain HB-23, a red solid. HB-23: Yield 71.2%; MS (ESI + ): C 52 H 75 N5O8 4+ (M / Z) 224.38; UV maximum absorption wavelength: 478nm, 568nm; fluorescence maximum emission wavelength: 629nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.35μM.

[0305] Example 27

[0306] 100mg HB-1b', 450mg cationic derivative 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide (DMSO) solution, thoroughly mixed, and stirred under nitrogen in the dark for 36 hours. After completion, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain HB-24, a red solid. HB-24: Yield 81.2%; MS (ESI + ): C 63 H 90 N5O 14 5+ (M / Z) 228.12; UV maximum absorption wavelength: 478nm, 561nm; fluorescence maximum emission wavelength: 650nm; minimum inhibitory concentration (MBC) for negative bacteria - Escherichia coli: 0.20μM; half inhibitory concentration (IC) for cholangiocarcinoma cell (RBE) 50 ):148nM.

[0307] Example 28

[0308] Dissolve 100 mg HB-1b and 62.1 mg trichloroacetonitrile in anhydrous dichloromethane, add 3 drops of BUN under ice bath, and react for 10 minutes. Separate the HB-1b trichloroacetonitrile derivative by column chromatography. The derivative was dissolved in acetonitrile. Five drops of TMSOTF were added dropwise at -40°C under nitrogen protection. The mixture was stirred in the dark for 0.5 h. After the reaction was complete, the acetonitrile was removed from the reaction system under reduced pressure to obtain a crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-25. HB-25: Yield 45.3%; MS (ESI + ): C 54 H 68 N4O 11 4+ (M / Z) 237.12; UV maximum absorption wavelength: 467nm, 556nm; fluorescence maximum emission wavelength: 618nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 0.35μM.

[0309] Example 29

[0310] 100mg HB-1c, 180mg cationic derivative 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide (DMSO) solution, thoroughly mixed, and stirred under nitrogen in the dark for 24 hours. After completion of the reaction, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain HB-26, a red solid. HB-26: Yield 75.3%; MS (ESI + ): C 64 H 90 N5O 10 5+ (M / Z) 217.73; UV maximum absorption wavelength: 477nm, 557nm; fluorescence maximum emission wavelength: 651nm; minimum inhibitory concentration (MBC) against negative bacteria - Bordetella pertussis: 0.25μM.

[0311] Example 30

[0312] 100mg HB-1a', 420mg cationic derivative The mixture was added to the dimethyl sulfoxide solution, mixed thoroughly, and refluxed in the dark under nitrogen for 12 hours. After completion of the reaction, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-27. HB-27: Yield 21.9%; MS (ESI + ): C 63 H 97 N9O9 8+(M / Z) 142.46; UV maximum absorption wavelength: 492nm, 575nm; fluorescence maximum emission wavelength: 665nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM.

[0313] Example 31

[0314] 100mg HB-1a', 380mg cationic derivative The mixture was added to the dimethyl sulfoxide solution, mixed thoroughly, and refluxed in the dark under nitrogen for 16 hours. After completion of the reaction, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-28. HB-28: Yield 32.6%; MS (ESI + ): C 54 H 73 N5O 11 4+ (M / Z) 241.88; UV maximum absorption wavelength: 491nm, 576nm; fluorescence maximum emission wavelength: 667nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40μM; half inhibitory concentration (IC) of esophageal cancer cells (KYSE-150) 50 ): 152nM.

[0315] Example 32

[0316] 100 mg of HB-1d acetonitrile solution was added dropwise to 290 mg of cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 54 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-29. HB-29: Yield 46.2%; MS (ESI + ): C 57 H 84 N5O8 5+ (M / Z) 193.32; UV maximum absorption wavelength: 478nm, 558nm; fluorescence maximum emission wavelength: 646nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.15μM.

[0317] Example 33

[0318] 100mg HB-1b, 320mg cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-30-N + , HB-30-2N + HB-30-N + : Yield: 79.2%; MS (ESI + ): C 54 H 74 N3O 10 3+ (M / Z) 308.17; UV maximum absorption wavelength: 473nm, 565nm; fluorescence maximum emission wavelength: 636nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-30-2N + : Yield: 73.2%; MS (ESI + ): C 66 H 100 N4O 10 4+ (M / Z) 277.18; UV maximum absorption wavelength: 470nm, 562nm; fluorescence maximum emission wavelength: 636nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM.

[0319] Example 34

[0320] 100 mg HB-1b and 62.1 mg trichloroacetonitrile were dissolved in anhydrous dichloromethane, 3 drops of BUN were added under ice bath, and the reaction was continued for 10 min. Column chromatography was used to separate the trichloroacetonitrile derivative of HB-1b. 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2) and the derivative were dissolved in acetonitrile solution, and 5 drops of TMSOTF were added dropwise at -40 ° C under nitrogen protection. The reaction was stirred in the dark for 0.5 h. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-31-N + HB-31-2N + HB-13-N + : Yield: 43.5%; MS (ESI + ): C 65 H 96 N3O 11 3+(M / Z) 364.90; UV maximum absorption wavelength: 468nm, 558nm; fluorescence maximum emission wavelength: 618nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-31-2N + : Yield: 38.1%; MS (ESI + ): C 85 H 138 N4O 11 4+ (M / Z) 347.75; UV maximum absorption wavelength: 472nm, 563nm; fluorescence maximum emission wavelength: 625nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.30μM.

[0321] Example 35

[0322] 100mg HB-1c, 320mg cationic derivative 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide (DMSO) solution, thoroughly mixed, and stirred under nitrogen in the dark for 40 hours. After completion, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the red solid product HB-32. HB-32: Yield 75.6%; MS (ESI + ): C 58 H 80 N4O 10 3+ (M / Z) 242.14; UV maximum absorption wavelength: 475nm, 566nm; fluorescence maximum emission wavelength: 638nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ):103nM.

[0323] Example 36

[0324] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-33 and HB-33-N, respectively. + HB-33-2N+ HB-33-4N + HB-33: yield 75.3%; MS (ESI + ): C 42 H 46 N4O6 2+ (M / Z) 351.17; UV maximum absorption wavelength: 460nm, 654nm; fluorescence maximum emission wavelength: 712nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-33-N + : Yield: 65.5%; MS (ESI + ): C 50 H 64 N5O6 3+ (M / Z) 276.82; UV maximum absorption wavelength: 462nm, 656nm; fluorescence maximum emission wavelength: 725nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-33-2N + : Yield: 62.0%; MS (ESI + ): C 58 H 82 N6O6 4+ (M / Z) 239.65; UV maximum absorption wavelength: 463nm, 657nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-33-4N + : Yield: 48.3%; MS (ESI + ): C 74 H 118 N8O6 6+ (M / Z) 202.48; UV maximum absorption wavelength: 472nm, 665nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM.

[0325] The preparation process of hypocrellin derivatives is shown in FIG2 .

[0326] Example 37

[0327] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-34 and HB-34-N, respectively. + HB-34-2N + HB-34-4N + HB-34: yield 68.2%; MS (ESI + ): C 43 H 52 N3O6 + (M / Z) 706.38; UV maximum absorption wavelength: 463nm, 655nm; fluorescence maximum emission wavelength: 716nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.95μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ):201nM. HB-34-N + : Yield: 66.5%; MS (ESI + ): C 51 H 70 N4O6 2+ (M / Z) 417.26; UV maximum absorption wavelength: 461nm, 656nm; fluorescence maximum emission wavelength: 720nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ):165nM. HB-34-2N + : Yield: 62.1%; MS (ESI + ): C 59 H 88 N5O6 3+ (M / Z) 320.89; UV maximum absorption wavelength: 462nm, 656nm; fluorescence maximum emission wavelength: 732nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ):139nM. HB-34-4N + : Yield: 49.3%; MS (ESI + ): C 74 H 122 N7O6 5+(M / Z) 240.98; UV maximum absorption wavelength: 473nm, 667nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431) 50 ): 121nM.

[0328] Example 38

[0329] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-35-N + HB-35-2N + HB-35-4N + HB-35-N + : Yield: 58.5%; MS (ESI + ): C 52 H 78 N6O6 4+ (M / Z) 220.64; UV maximum absorption wavelength: 462nm, 657nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-35-2N + : Yield: 46.1%; MS (ESI + ): C 68 H 114 N8O6 6+ (M / Z) 189.81; UV maximum absorption wavelength: 464nm, 656nm; fluorescence maximum emission wavelength: 720nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM. HB-35-4N + : Yield: 36.5%; MS (ESI + ): C 100 H 186 N 12 O6 10+ (M / Z) 165.24; UV maximum absorption wavelength: 475nm, 668nm; fluorescence maximum emission wavelength: 732nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.01μM.

[0330] Example 39

[0331] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-36-N + HB-36-2N + HB-36-4N + HB-36-N + : Yield: 66.5%; MS (ESI + ): C 46 H 60 N4O7 2+ (M / Z) 390.22; UV maximum absorption wavelength: 460nm, 655nm; fluorescence maximum emission wavelength: 724nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 1.55μM; half inhibitory concentration (IC 50 ):154nM. HB-36-2N + : Yield: 52.1%; MS (ESI + ): C 56 H 82 N5O7 3+ (M / Z) 312.20; UV maximum absorption wavelength: 461nm, 656nm; fluorescence maximum emission wavelength: 720nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.55μM; half inhibitory concentration (IC 50 ):109nM. HB-36-4N + : Yield: 36.5%; MS (ESI + ): C 76 H 126 N7O7 4+ (M / Z) 249.79; UV maximum absorption wavelength: 475nm, 668nm; fluorescence maximum emission wavelength: 732nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.35μM; half inhibitory concentration (IC 50 ):87nM.

[0332] Example 40

[0333] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-37-N + HB-37-2N + HB-37-4N + HB-37-N + : Yield: 68.5%; MS (ESI + ): C 52 H 64 N4O7S 2+ (M / Z) 444.22; UV maximum absorption wavelength: 462nm, 657nm; fluorescence maximum emission wavelength: 718nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.50μM. HB-37-2N + : Yield: 58.3%; MS (ESI + ): C 60 H 82 N5O7S 3+ (M / Z) 338.86; UV maximum absorption wavelength: 463nm, 659nm; fluorescence maximum emission wavelength: 722nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-37-4N + : Yield: 39.2%; MS (ESI + ): C 76 H 118 N7O7S 5+ (M / Z) 254.57; UV maximum absorption wavelength: 478nm, 669nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM.

[0334] Example 41

[0335] 100mg of hypocrellin derivatives, 350mg of cationic derivatives 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide (DMSO) solution, thoroughly mixed, and stirred under nitrogen in the dark for 48 hours. After completion, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain HB-38, a red solid. HB-38: Yield 78.3%; MS (ESI + ): C 57 H 84 N8O8 4+ (M / Z) 252.15; UV maximum absorption wavelength: 479nm, 659nm; fluorescence maximum emission wavelength: 756nm; minimum inhibitory concentration (MBC) against negative bacteria - Neisseria meningitidis: 0.35μM.

[0336] Example 42

[0337] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-39 and HB-39-N, respectively. + HB-39-2N + HB-39-4N + HB-39: yield 71.0%; MS (ESI + ): C 56 H 64 N4O6 2+ (M / Z) 444.24; UV maximum absorption wavelength: 466nm, 658nm; fluorescence maximum emission wavelength: 716nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.50μM. HB-39-N + : Yield: 61.2%; MS (ESI + ): C 68 H 88 N6O6 4+ (M / Z) 271.16; UV maximum absorption wavelength: 468nm, 659nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-39-2N + : Yield: 58.3%; MS (ESI + ): C80 H 112 N8O6 6+ (M / Z) 213.47; UV maximum absorption wavelength: 468nm, 657nm; fluorescence maximum emission wavelength: 729nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM. HB-39-4N + : Yield: 43.6%; MS (ESI + ): C 104 H 160 N 12 O6 10+ (M / Z) 167.42; UV maximum absorption wavelength: 473nm, 667nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.01μM.

[0338] Example 43

[0339] 100 mg of hypocrellin derivative acetonitrile solution was added dropwise to 300 mg of cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 48 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-40. HB-40: Yield 35.6%; MS (ESI + ): C 62 H 92 N8O 13 S2 6+ (M / Z) 203.43; UV maximum absorption wavelength: 466nm, 663nm; fluorescence maximum emission wavelength: 733nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.10μM; HeLa cell half inhibitory concentration (IC 50 ):148nM.

[0340] Example 44

[0341] 100 mg of hypocrellin derivative and 62.1 mg of trichloroacetonitrile were dissolved in anhydrous dichloromethane, 3 drops of BUN were added under ice bath, and the reaction was continued for 10 min. Hypocrellin trichloroacetonitrile derivative was obtained by column chromatography. 270 mg of cationic derivative ( n is 1, 2 or 3) and the derivative were dissolved in acetonitrile solution, 5 drops of TMSOTF were added dropwise at -40°C under nitrogen protection, and the reaction was stirred in the dark for 0.5h. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-41-N + HB-41-2N + HB-41-3N + HB-41-N + : Yield: 69.6%; MS (ESI + ): C 41 H 46 N4O9 2+ (M / Z) 369.16; UV maximum absorption wavelength: 463nm, 658nm; fluorescence maximum emission wavelength: 719nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-41-2N + : Yield: 56.7%; MS (ESI + ): C 49 H 62 N6O9 4+ (M / Z) 219.61; UV maximum absorption wavelength: 465nm, 658nm; fluorescence maximum emission wavelength: 723nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-41-3N + : Yield: 38.6%; MS (ESI + ): C 57 H 78 N8O9 6+ (M / Z) 169.76; UV maximum absorption wavelength: 479nm, 672nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM.

[0342] Example 45

[0343] 100 mg of hypocrellin derivative and 62.1 mg of trichloroacetonitrile were dissolved in anhydrous dichloromethane, 3 drops of BUN were added under ice bath, and the reaction was continued for 10 min. Hypocrellin trichloroacetonitrile derivative was obtained by column chromatography. 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 3) and the derivative were dissolved in acetonitrile solution, 5 drops of TMSOTF were added dropwise at -40 ° C under nitrogen protection, and the reaction was stirred in the dark for 0.5 h. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The obtained crude product was further separated by silica gel plate chromatography to obtain black solid products HB-42-N +HB-42-2N + HB-42-3N + HB-42-N + : Yield: 56.8%; MS (ESI + ): C 68 H 76 N4O7PS 3+ (M / Z) 374.50; UV maximum absorption wavelength: 461nm, 657nm; fluorescence maximum emission wavelength: 718nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-42-2N + : Yield: 41.2%; MS (ESI + ): C 80 H 100 N6O7PS 5+ (M / Z) 263.94; UV maximum absorption wavelength: 462nm, 658nm; fluorescence maximum emission wavelength: 722nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20μM. HB-42-3N + : Yield: 28.3%; MS (ESI + ): C 92 H 124 N8O7PS 7+ (M / Z) 216.55; UV maximum absorption wavelength: 475nm, 668nm; fluorescence maximum emission wavelength: 730nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM.

[0344] Example 46

[0345] 100 mg of hypocrellin derivative, 380 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2) in dimethyl sulfoxide solution, after thorough mixing, under nitrogen protection, reflux in the dark for 26 hours. After the reaction is completed, the mixture solution is extracted with H2O and DCM, the aqueous phase is collected, and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-43-N + HB-43-2N + HB-43-N + : Yield: 41.2%; MS (ESI + ): C 52 H 69 N6O8 3+(M / Z) 301.83; UV maximum absorption wavelength: 461nm, 659nm; fluorescence maximum emission wavelength: 723nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.55μM. HB-43-2N + : Yield: 28.3%; MS (ESI + ): C 70 H 107 N9O8 6+ (M / Z) 200.30; UV maximum absorption wavelength: 476nm, 669nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.10μM.

[0346] Example 47

[0347] 100 mg of hypocrellin derivative, 380 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2) in dimethyl sulfoxide solution, after thorough mixing, under nitrogen protection, reflux in the dark for 26 hours. After the reaction is completed, the mixture solution is extracted with H2O and DCM, the aqueous phase is collected, and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-44-N + HB-44-2N + HB-44-N + : Yield: 36.2%; MS (ESI + ): C 45 H 53 N5O7 2+ (M / Z) 387.69; UV maximum absorption wavelength: 464nm, 661nm; fluorescence maximum emission wavelength: 725nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 1.55μM; half inhibitory concentration (IC) of cholangiocarcinoma cells (HCCC-9810) 50 ):148nM. HB-44-2N + : Yield: 24.2%; MS (ESI + ): C 57 H 77 N7O7 4+ (M / Z) 242.89; UV maximum absorption wavelength: 478nm, 671nm; fluorescence maximum emission wavelength: 733nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 0.35μM; half inhibitory concentration (IC) of cholangiocarcinoma cells (HCCC-9810) 50 ): 95nM.

[0348] Example 48

[0349] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 32 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-45-N + HB-45-2N + HB-45-N + : Yield: 75.6%; MS (ESI + ): C 64 H 76 N5O9 3+ (M / Z) 352.85; UV maximum absorption wavelength: 466nm, 659nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.55μM. HB-45-2N + : Yield: 68.2%; MS (ESI + ): C 77 H 102 N7O9 5+ (M / Z) 253.75; UV maximum absorption wavelength: 470nm, 664nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.20μM.

[0350] Example 49

[0351] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 32 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-46-N + HB-46-2N + HB-46-N + : Yield: 78.2%; MS (ESI + ): C 48 H 60 N4O9 2+(M / Z) 418.21; UV maximum absorption wavelength: 465nm, 662nm; fluorescence maximum emission wavelength: 725nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-46-2N + : Yield: 69.5%; MS (ESI + ): C 62 H 88 N6O9 4+ (M / Z) 265.16; UV maximum absorption wavelength: 469nm, 666nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM.

[0352] Example 50

[0353] 100 mg of hypocrellin derivative, 310 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-47-N + HB-47-2N + HB-47-N + : Yield: 68.2%; MS (ESI + ): C 56 H 75 N5O 12 2+ (M / Z) 504.77; UV maximum absorption wavelength: 465nm, 660nm; fluorescence maximum emission wavelength: 721nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 1.50μM. HB-47-2N + : Yield: 55.6%; MS (ESI + ): C 69 H 101 N7O 12 4+ (M / Z) 304.93; UV maximum absorption wavelength: 470nm, 666nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.35μM.

[0354] Example 51

[0355] 100 mg of hypocrellin derivative, 370 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain red solid products HB-48-N + HB-48-2N + HB-48-N + : Yield: 63.5%; MS (ESI + ): C 60 H 83 N5O 12 2+ (M / Z) 532.80; UV maximum absorption wavelength: 466nm, 661nm; fluorescence maximum emission wavelength: 722nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.45μM. HB-48-2N + : Yield: 53.1%; MS (ESI + ): C 69 H 101 N7O 12 4+ (M / Z) 304.93; UV maximum absorption wavelength: 468nm, 668nm; fluorescence maximum emission wavelength: 728nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.30μM.

[0356] Example 52

[0357] 100 mg of hypocrellin derivative acetonitrile solution was added dropwise to 300 mg of cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 48 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-49. HB-49: Yield 39.5%; MS (ESI + ): C 82 H 136 N 10 O9 8+(M / Z) 175.63; UV maximum absorption wavelength: 468nm, 669nm; fluorescence maximum emission wavelength: 738nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 0.05μM; half inhibitory concentration (IC) of cholangiocarcinoma cells (HCCC-9810) 50 ): 115nM.

[0358] Example 53

[0359] 100 mg of hypocrellin derivative acetonitrile solution was added dropwise to 300 mg of cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 48 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-50. HB-50: Yield 41.5%; MS (ESI + ): C 96 H 154 N 12 O6 10+ (M / Z) 157.22; UV maximum absorption wavelength: 471nm, 672nm; fluorescence maximum emission wavelength: 741nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.01μM.

[0360] Example 54

[0361] 100 mg of hypocrellin derivative acetonitrile solution was added dropwise to 300 mg of cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 48 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-51. HB-51: Yield 36.1%; MS (ESI + ): C 84 H 142 N 14 O8 8+ (M / Z) 184.38; UV maximum absorption wavelength: 472nm, 673nm; fluorescence maximum emission wavelength: 740nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 0.05μM.

[0362] Example 55

[0363] 100mg of hypocrellin derivatives, 360mg of cationic derivatives 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide (DMSO) solution, thoroughly mixed, and stirred under nitrogen in the dark for 32 hours. After completion, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain HB-52, a red solid. HB-52: Yield 69.1%; MS (ESI + ): C 60 H 83 N6O 13 3+ (M / Z) 365.20; UV maximum absorption wavelength: 466nm, 665nm; fluorescence maximum emission wavelength: 728nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.55μM.

[0364] Example 56

[0365] 100 mg of hypocrellin derivative and 62.1 mg of trichloroacetonitrile were dissolved in anhydrous dichloromethane, 3 drops of BUN were added under ice bath, and the mixture was reacted for 10 min. Hypocrellin trichloroacetonitrile derivative was obtained by column chromatography. 270 mg of cationic derivative was added. The derivative was dissolved in acetonitrile, and 5 drops of TMSOTF were added dropwise at -40°C under nitrogen. The mixture was stirred in the dark for 0.5 h. After the reaction was complete, the acetonitrile was removed from the reaction system under reduced pressure to obtain a crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-53. HB-53: Yield 35.1%; MS (ESI + ): C 61 H 84 N6O 10 4+ (M / Z) 265.15; UV maximum absorption wavelength: 462nm, 659nm; fluorescence maximum emission wavelength: 721nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.30μM.

[0366] Example 57

[0367] 100mg of hypocrellin derivatives, 380mg of cationic derivatives After thorough mixing, the mixture was refluxed in the dark under nitrogen for 26 hours. After completion of the reaction, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain a crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-54. HB-54: Yield 36.2%; MS (ESI + ): C 56 H 77 N7O9 4+ (M / Z) 247.89; UV maximum absorption wavelength: 465nm, 662nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431) 50 ):168nM.

[0368] Example 58

[0369] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-55 and HB-55-N, respectively. + HB-55-2N + HB-55-4N + HB-55: yield 73.5%; MS (ESI + ): C 43 H 47 N3O7S 2+ (M / Z) 374.65; UV maximum absorption wavelength: 532nm, 665nm; fluorescence maximum emission wavelength: 718nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 1.55μM; half inhibitory concentration (IC 50 ):235nM. HB-55-N + : Yield: 63.5%; MS (ESI + ): C 51 H 65 N4O7S 3+(M / Z) 292.48; UV maximum absorption wavelength: 535nm, 666nm; fluorescence maximum emission wavelength: 725nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.55μM; half inhibitory concentration (IC 50 ):197nM. HB-55-2N + : Yield: 58.3%; MS (ESI + ): C 59 H 83 N5O7S 4+ (M / Z) 251.39; UV maximum absorption wavelength: 542nm, 667nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.35μM; half inhibitory concentration (IC 50 ):189nM. HB-55-4N + : Yield: 49.3%; MS (ESI + ): C 67 H 101 N6O7S 5+ (M / Z) 226.74; UV maximum absorption wavelength: 538nm, 668nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.15μM; half inhibitory concentration (IC 50 ):167nM.

[0370] Example 59

[0371] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-56 and HB-56-N, respectively. + HB-56-2N + HB-56-4N + HB-56: yield 72.1%; MS (ESI + ): C 40 H 47 N2O7S +(M / Z) 699.30; UV maximum absorption wavelength: 530nm, 662nm; fluorescence maximum emission wavelength: 720nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.85μM. HB-56-N + : Yield: 68.2%; MS (ESI + ): C 48 H 65 N3O7S 2+ (M / Z) 413.72; UV maximum absorption wavelength: 532nm, 663nm; fluorescence maximum emission wavelength: 723nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.55μM. HB-56-2N + : Yield: 56.3%; MS (ESI + ): C 56 H 83 N4O7S 3+ (M / Z) 318.53; UV maximum absorption wavelength: 538nm, 668nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-56-4N + : Yield: 46.2%; MS (ESI + ): C 72 H 119 N6O7S 5+ (M / Z) 242.37; UV maximum absorption wavelength: 539nm, 672nm; fluorescence maximum emission wavelength: 738nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM.

[0372] Example 60

[0373] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-57-N + HB-57-2N + HB-57-4N + HB-57-N + : Yield: 65.8%; MS (ESI + ): C 43 H 54 N4O6S22+ (M / Z) 393.17; UV maximum absorption wavelength: 582nm, 693nm; fluorescence maximum emission wavelength: 717nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 1.55μM. HB-57-2N + : Yield: 52.3%; MS (ESI + ): C 51 H 72 N5O6S2 3+ (M / Z) 304.83; UV maximum absorption wavelength: 588nm, 697nm; fluorescence maximum emission wavelength: 725nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 0.60μM. HB-57-4N + : Yield: 46.2%; MS (ESI + ): C 67 H 108 N7O6S2 5+ (M / Z) 234.15; UV maximum absorption wavelength: 589nm, 698nm; fluorescence maximum emission wavelength: 728nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 0.20μM.

[0374] The preparation process of hypocrellin derivatives is shown in FIG3 .

[0375] Example 61

[0376] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-58-N + HB-58-2N + HB-58-4N + HB-58-N + : Yield: 62.1%; MS (ESI + ): C 48 H 63 N3O8S 2+ (M / Z) 420.71; UV maximum absorption wavelength: 531nm, 664nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.50μM. HB-58-2N +: Yield: 52.3%; MS (ESI + ): C 58 H 85 N4O8S 3+ (M / Z) 332.53; UV maximum absorption wavelength: 539nm, 669nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-58-4N + : Yield: 46.9%; MS (ESI + ): C 78 H 129 N6O8S 5+ (M / Z) 261.99; UV maximum absorption wavelength: 542nm, 673nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM.

[0377] Example 62

[0378] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-59 and HB-59-N, respectively. + HB-59-2N + HB-59: yield 61.2%; MS (ESI + ): C 45 H 55 N4O8S 3+ (M / Z) 270.45; UV maximum absorption wavelength: 532nm, 663nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-59-N + : Yield: 52.3%; MS (ESI + ): C 54 H 75 N5O8S 4+ (M / Z) 238.38; UV maximum absorption wavelength: 535nm, 666nm; fluorescence maximum emission wavelength: 728nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-59-2N + : Yield: 45.3%; MS (ESI+ ): C 62 H 93 N6O8S 5+ (M / Z) 216.33; UV maximum absorption wavelength: 538nm, 670nm; fluorescence maximum emission wavelength: 730nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20μM.

[0379] Example 63

[0380] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 32 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-60-N + HB-60-3N + HB-60-N + : Yield: 56.3%; MS (ESI + ): C 49 H 63 N2O9S + (M / Z) 855.42; UV maximum absorption wavelength: 536nm, 668nm; fluorescence maximum emission wavelength: 729nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 1.95μM. HB-60-3N + : Yield: 36.3%; MS (ESI + ): C 73 H 115 N4O9S 3+ (M / Z) 407.94; UV maximum absorption wavelength: 539nm, 673nm; fluorescence maximum emission wavelength: 734nm; minimum inhibitory concentration (MBC) against negative bacteria - Proteus: 0.55μM.

[0381] Example 64

[0382] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-61 and HB-61-N, respectively. + HB-61-2N + HB-61: Yield 86.3%; MS (ESI + ): C 53 H 62 N5O8S2 3+ (M / Z) 320.13; UV maximum absorption wavelength: 584nm, 696nm; fluorescence maximum emission wavelength: 723nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-61-N + : Yield: 75.6%; MS (ESI + ): C 79 H 116 N6O8S2 4+ (M / Z) 335.20; UV maximum absorption wavelength: 586nm, 699nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM. HB-61-2N + : Yield: 66.3%; MS (ESI + ): C 105 H 170 N7O8S2 5+ (M / Z) 344.45; UV maximum absorption wavelength: 580nm, 699nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20μM.

[0383] Example 65

[0384] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-62-N + HB-62-2N + HB-62-N +: Yield: 86.6%; MS (ESI + ): C 72 H 108 N3O 14 3+ (M / Z) 423.57; UV maximum absorption wavelength: 587nm, 701nm; fluorescence maximum emission wavelength: 751nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 0.50μM. HB-62-2N + : Yield: 67.3%; MS (ESI + ): C 87 H 144 N6O 14 6+ (M / Z) 254.83; UV maximum absorption wavelength: 589nm, 702nm; fluorescence maximum emission wavelength: 759nm; minimum inhibitory concentration (MBC) against positive bacteria - Staphylococcus aureus: 0.10μM.

[0385] Example 66

[0386] 100 mg of hypocrellin derivative, 310 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 25.1 mg of NHS were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-63-N + HB-63-2N + HB-63-N + : Yield: 68.3%; MS (ESI + ): C 83 H 128 N5O 10 S 3+ (M / Z) 462.31; UV maximum absorption wavelength: 535nm, 667nm; fluorescence maximum emission wavelength: 726nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-63-2N + : Yield: 59.3%; MS (ESI + ): C 117 H 198 N6O 10 S 4+(M / Z) 470.12; UV maximum absorption wavelength: 538nm, 672nm; fluorescence maximum emission wavelength: 730nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35μM.

[0387] Example 67

[0388] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2) in a mixed solution of acetonitrile: dimethyl sulfoxide (3:1), heated to 55°C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-64 and HB-64-N, respectively. + HB-64-2N + HB-64: yield 72.2%; MS (ESI + ): C 43 H 43 N2O9S + (M / Z) 763.26; UV maximum absorption wavelength: 533nm, 666nm; fluorescence maximum emission wavelength: 725nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.75μM. HB-64-N + : Yield: 58.3%; MS (ESI + ): C 55 H 67 N4O9S 3+ (M / Z) 319.82; UV maximum absorption wavelength: 536nm, 668nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-64-2N + : Yield: 38.3%; MS (ESI + ): C 66 H 89 N6O9S 5+ (M / Z) 228.32; UV maximum absorption wavelength: 539nm, 672nm; fluorescence maximum emission wavelength: 733nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20μM.

[0389] Example 68

[0390] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-65-N + HB-65-2N + HB-65-4N + HB-65-N + : Yield: 63.5%; MS (ESI + ): C 62 H 87 N4O 12 S 3+ (M / Z) 370.53; UV maximum absorption wavelength: 535nm, 668nm; fluorescence maximum emission wavelength: 728nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.55μM. HB-65-2N + : Yield: 53.3%; MS (ESI + ): C 72 H 107 N6O 12 S 5+ (M / Z) 255.95; UV maximum absorption wavelength: 538nm, 669nm; fluorescence maximum emission wavelength: 732nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM. HB-65-4N + : Yield: 35.3%; MS (ESI + ):

[0391] C 93 H 149 N 10 O 12 S 9+ (M / Z) 181.23; UV maximum absorption wavelengths: 542 nm, 675 nm; fluorescence maximum emission wavelength: 736 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05 μM.

[0392] Example 69

[0393] 100 mg of hypocrellin derivative and 62.1 mg of trichloroacetonitrile were dissolved in anhydrous dichloromethane, 3 drops of BUN were added under ice bath, and the reaction was continued for 10 min. Hypocrellin trichloroacetonitrile derivative was obtained by column chromatography. 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 3) and the derivative were dissolved in acetonitrile solution, 5 drops of TMSOTF were added dropwise under nitrogen protection at -40 ° C, and the reaction was stirred in the dark for 0.5 hours. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The obtained crude product was further separated by silica gel plate chromatography to obtain black solid products HB-66-N + HB-66-3N + HB-66-N + : Yield: 68.2%; MS (ESI + ): C 49 H 58 N4O 10 S2 2+ (M / Z) 463.17; UV maximum absorption wavelength: 537nm, 687nm; fluorescence maximum emission wavelength: 747nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 1.50μM; HeLa cell half inhibitory concentration (IC 50 ):167nM. HB-66-3N + : Yield: 45.1%; MS (ESI + ): C 65 H 90 N8O 10 S2 6+ (M / Z) 201.10; UV maximum absorption wavelength: 539nm, 688nm; fluorescence maximum emission wavelength: 750nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.10μM; HeLa cell half inhibitory concentration (IC 50 ):103nM.

[0394] Example 70

[0395] 100 mg of hypocrellin derivative and 62.1 mg of trichloroacetonitrile were dissolved in anhydrous dichloromethane, 3 drops of BUN were added under ice bath, and the reaction was continued for 10 min. Hypocrellin trichloroacetonitrile derivative was obtained by column chromatography. 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) and the derivative were dissolved in acetonitrile solution, 5 drops of TMSOTF were added dropwise at -40 ° C under nitrogen protection, and the reaction was stirred in the dark for 0.5 h. After the reaction was completed, the reaction system was distilled under reduced pressure to remove acetonitrile to obtain a crude product. The obtained crude product was further separated by silica gel plate chromatography to obtain black solid products HB-67-N + HB-67-2N + HB-67-4N + HB-67-N + : Yield: 43.5%; MS (ESI + ): C72 H 85 N3O8PS2 3+ (M / Z) 404.85; UV maximum absorption wavelength: 541nm, 672nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-67-2N + : Yield: 35.4%; MS (ESI + ): C 88 H 117 N5O8PS2 5+ (M / Z) 293.36; UV maximum absorption wavelength: 543nm, 675nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15μM. HB-67-4N + : Yield: 28.1%; MS (ESI + ): C 120 H 181 N9O8PS2 9+ (M / Z) 219.14; UV maximum absorption wavelength: 545nm, 676nm; fluorescence maximum emission wavelength: 737nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.05μM.

[0396] Example 71

[0397] 100 mg of hypocrellin derivative, 380 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 3) in dimethyl sulfoxide solution, after thorough mixing, under nitrogen protection, reflux in the dark for 26 hours. After the reaction is completed, the mixture solution is extracted with H2O and DCM, the aqueous phase is collected, and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-68 and HB-68-N + HB-68-3N + HB-68: yield 52.5%; MS (ESI + ): C 38 H 41 N4O6S2 + (M / Z) 713.24; UV maximum absorption wavelength: 546nm, 688nm; fluorescence maximum emission wavelength: 740nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 1.90μM. HB-68-N + : Yield: 42.5%; MS (ESI + ): C 48 H 61 N6O6S2 3+(M / Z) 293.80; UV maximum absorption wavelength: 548nm, 689nm; fluorescence maximum emission wavelength: 748nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.55μM. HB-68-3N + : Yield: 25.3%; MS (ESI + ): C 68 H 101 N 10 O6S2 7+ (M / Z) 173.96; UV maximum absorption wavelength: 552nm, 688nm; fluorescence maximum emission wavelength: 749nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.05μM.

[0398] Example 72

[0399] 100 mg of hypocrellin derivative, 380 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2) in dimethyl sulfoxide solution, after thorough mixing, under nitrogen protection, reflux in the dark for 26 hours. After the reaction is completed, the mixture solution is extracted with H2O and DCM, the aqueous phase is collected, and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain a black solid product HB-69-N + HB-69-2N + HB-69-N + : Yield: 31.5%; MS (ESI + ): C 78 H 115 N 11 O7S2 6+ (M / Z) 230.30; UV maximum absorption wavelength: 552nm, 682nm; fluorescence maximum emission wavelength: 742nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM. HB-69-2N + : Yield: 21.6%; MS (ESI + ): C 111 H 181 N 17 O7S2 12+ (M / Z) 160.78; UV maximum absorption wavelength: 558nm, 689nm; fluorescence maximum emission wavelength: 746nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.01μM.

[0400] Example 73

[0401] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-70-N + HB-70-2N + HB-70-N + : Yield: 83.5%; MS (ESI + ): C 87 H 117 N7O 16 S 6+ (M / Z) 257.97; UV maximum absorption wavelength: 575nm, 696nm; fluorescence maximum emission wavelength: 722nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.10μM. HB-70-2N + : Yield: 65.2%; MS (ESI + ): C 115 H 173 N 11 O 16 S 10+ (M / Z) 199.72; UV maximum absorption wavelength: 582nm, 699nm; fluorescence maximum emission wavelength: 731nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.03μM.

[0402] Example 4a

[0403] The preparation method for compounds HB-1 and HB-1' was based on the reference (Bioorganic & Medicinal Chemistry Letters 11 (2001) 2045–2047), with appropriate modifications. HB (300 mg) and cyclohexylamine (6 mL) were dissolved in anhydrous tetrahydrofuran (20 mL) and heated to 55°C. Stirred under nitrogen, in the dark, for 6 hours. After removing the solvent under reduced pressure, the mixture was extracted with dichloromethane, dried, and spin-dried. The remaining black solid was separated by column chromatography to yield the compounds. The synthetic steps for the following examples involving hypocrellin derivatives substituted at the 2nd position with an amino derivative are essentially the same as those for the preparation of compounds HB-1 and HB-1'.

[0404] The preparation method for HB-1a (HB-1a') was based on the reference (Organic Chemistry, 1990, 10, 339-342), with appropriate modifications: 100 mg of HB-1 (or HB-1'), 100 mg of selenium dioxide, and 8 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 6 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, and the mixture was extracted three times with 100 mL of dichloromethane. The organic layer was dried on a rotary evaporator to obtain a black solid, which was then separated and purified to obtain HB-1a (HB-1a').

[0405] Preparation of HB-1b (HB-1b'): 100 mg of HB-1 (or HB-1b'), 48 mg of selenium dioxide, and 25 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 1.5 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic layer was dried using a rotary evaporator to obtain a black solid. After separation and purification, 75 mg of HB-1b and 16 mg of HB-1a were obtained.

[0406] Preparation of HB-1c (HB-1c'): 100 mg of HB-1 (HB-1'), 120 mg of selenium dioxide, and 8 mL of 1,4-dioxane were added to a two-necked flask and heated under reflux for 15 hours before terminating the reaction. 100 mL of ultrapure water was added to the reaction solution, and the mixture was extracted three times with 100 mL of dichloromethane. The organic layer was dried using a rotary evaporator to obtain a black solid. This was then separated and purified to obtain 1 mg of HB-1c (HB-1c').

[0407] Preparation of HB-1d (HB-1d'): Dissolve 100 mg of HB-1b (HB-1b' is used as a raw material in the preparation of HB-1d') and 100 mg of carbon tetrabromide in anhydrous dichloromethane. Stir at room temperature for 6 h under anhydrous and oxygen-free conditions. The organic layer is dried using a rotary evaporator to obtain a black solid, which is separated and purified to obtain HB-1d (HB-1d').

[0408] Example 5a

[0409] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 300 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 50 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-2a and HB-2a-N, respectively. + HB-2a-2N +HB-2a-4N + HB-2a: yield 70.1%; MS (ESI + ): C 41 H 44 N2O8 2+ (M / Z) 346.15; UV maximum absorption wavelength: 582 nm; fluorescence maximum emission wavelength: 752 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.45 μM; HeLa cell half inhibitory concentration (IC 50 ):204nM. HB-2a-N + : Yield: 65.4%; MS (ESI + ): C 49 H 62 N3O8 3+ (M / Z) 273.48; UV maximum absorption wavelength: 586 nm; fluorescence maximum emission wavelength: 755 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.45 μM; HeLa cell half inhibitory concentration (IC 50 ):115nM. HB-2a-2N + : Yield: 54.0%; MS (ESI + ): C 57 H 80 N4O8 4+ (M / Z) 237.15; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 751 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.25 μM; HeLa cell half inhibitory concentration (IC 50 ):102nM. HB-2a-4N + : Yield: 34.0%; MS (ESI + ): C 73 H 116 N6O8 6+ (M / Z) 200.81; UV maximum absorption wavelength: 595 nm; fluorescence maximum emission wavelength: 760 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 100 nM; HeLa cell half inhibitory concentration (IC 50 ): 99nM.

[0410] Example 6a

[0411] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 2:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 52 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-3a-N + HB-3a-2N + HB-3a-4N + HB-3a-N + : Yield: 68.4%; MS (ESI + ): C 44 H 58 N2O8 2+ (M / Z) 371.21; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.35 μM; half inhibitory concentration (IC 50 ):156nM. HB-3a-2N + : Yield: 58.8%; MS (ESI + ): C 52 H 76 N3O8 3+ (M / Z) 290.19; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 746 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35 μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ):124nM. HB-3a-4N + : Yield: 38.0%; MS (ESI + ): C 68 H 112 N5O8 5+ (M / Z) 225.37; UV maximum absorption wavelength: 596 nm; fluorescence maximum emission wavelength: 755 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15 μM; half inhibitory concentration (IC 50 ): 102nM.

[0412] Example 7a

[0413] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 330 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 52 ° C under nitrogen protection, and stirred in the dark for 45 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-4a-N + HB-4a-2N + HB-4a-4N + HB-4a-N + : Yield: 69.5%; MS (ESI + ): C 39 H 48 N2O8 2+ (M / Z) 336.17; UV maximum absorption wavelength: 586 nm; fluorescence maximum emission wavelength: 755 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.40 μM. HB-4a-2N + : Yield: 50.2%; MS (ESI + ): C 46 H 64 N3O8 3+ (M / Z) 262.16; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 754 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40 μM. HB-4a-4N + : Yield: 24.0%; MS (ESI + ): C 63 H 102 N5O8 5+ (M / Z) 211.35; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 770 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15 μM.

[0414] Example 8a

[0415] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 350 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 2.5:1), heated to 50 ° C under nitrogen protection, and stirred in the dark for 45 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-5a-N + HB-5a-2N +HB-5a-4N + HB-5a-N + : Yield: 61.7%; MS (ESI + ): C 48 H 65 N3O8 2+ (M / Z) 405.74; UV maximum absorption wavelength: 580nm; fluorescence maximum emission wavelength: 740nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.45μM. HB-5a-2N + : Yield: 48.5%; MS (ESI + ): C 58 H 87 N4O8 3+ (M / Z) 322.55; UV maximum absorption wavelength: 583 nm; fluorescence maximum emission wavelength: 742 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.45 μM. HB-5a-4N + : Yield: 38.5%; MS (ESI + ): C 78 H 131 N6O8 5+ (M / Z) 256.00; UV maximum absorption wavelength: 587 nm; fluorescence maximum emission wavelength: 746 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20 μM.

[0416] Example 9a

[0417] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 350 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 56 ° C under nitrogen protection, and stirred in the dark for 60 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-6a and HB-6a-N, respectively. + HB-6a-2N + HB-6a-4N + HB-6a: yield 75.4%; MS (ESI + ): C 45 H 56 N4O9 2+(M / Z) 398.20; UV maximum absorption wavelength: 585nm; fluorescence maximum emission wavelength: 735nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.35μM. HB-6a-N + : Yield: 54.5%; MS (ESI + ): C 53 H 74 N5O9 3+ (M / Z) 308.18; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 736 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35 μM. HB-6a-2N + : Yield: 53.0%; MS (ESI + ): C 61 H 92 N6O9 4+ (M / Z) 263.17; UV maximum absorption wavelength: 591 nm; fluorescence maximum emission wavelength: 738 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.25 μM. HB-6a-4N + : Yield: 35.6%; MS (ESI + ): C 77 H 128 N8O9 6+ (M / Z) 218.16; UV maximum absorption wavelength: 593 nm; fluorescence maximum emission wavelength: 740 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 95 nM.

[0418] Example 10a

[0419] 100 mg of hypocrellin derivative, 156 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 36 hours. After the reaction was completed, the mixture was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-7a-2N + HB-7a-3N + HB-7a-2N + : Yield: 64.5%; MS (ESI + ): C 77 H 125 N5O 11 4+(M / Z) 323.98; UV maximum absorption wavelength: 586nm; fluorescence maximum emission wavelength: 739nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.30μM. HB-7a-3N + : Yield: 35.4%; MS (ESI + ): C 97 H 169 N7O 11 6+ (M / Z) 268.21; UV maximum absorption wavelength: 585 nm; fluorescence maximum emission wavelength: 741 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 105 nM.

[0420] Example 11a

[0421] Containing 100mg of hypocrellin derivative, 350mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 24 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-8a-N + HB-8a-2N + 、HB-8a-4N + HB-8a-N + : Yield: 75.8%; MS (ESI + ): C 56 H 71 N3O9 2+ (M / Z) 464.76; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.40 μM. HB-8a-2N + : Yield: 63.6%; MS (ESI + ): C 70 H 101 N4O9 3+ (M / Z) 380.59; UV maximum absorption wavelength: 589nm; fluorescence maximum emission wavelength: 746nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40μM. HB-8a-4N + : Yield: 35.7%; MS (ESI + ): C 98 H 161 N6O9 5+(M / Z) 313.45; UV maximum absorption wavelength: 591 nm; fluorescence maximum emission wavelength: 748 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15 μM.

[0422] Example 12a

[0423] Containing 100mg of hypocrellin derivative, 200mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 28 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-9a-2N + HB-9a-3N + HB-9a-2N + : Yield: 46.7%; MS (ESI + ): C 60 H 91 N5O 10 4+ (M / Z) 260.42; UV maximum absorption wavelength: 586 nm; fluorescence maximum emission wavelength: 744 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.30 μM; half inhibitory concentration (IC 50 ):167nM. HB-9a-3N + : Yield: 29.6%; MS (ESI + ): C 70 H 115 N7O 10 6+ (M / Z) 202.31; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 105 nM; half inhibitory concentration (IC) of esophageal cancer cells (KYSE-150) 50 ):135nM.

[0424] Example 13a

[0425] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 350 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 56 ° C under nitrogen protection, and stirred in the dark for 60 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-10a and HB-10a-N, respectively. + HB-10a-2N + HB-10a: yield 83.6%; MS (ESI + ): C 56 H 71 N5O7 4+ (M / Z) 231.38; UV maximum absorption wavelength: 585nm; fluorescence maximum emission wavelength: 745nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.25μM. HB-10a-N + : Yield: 52.1%; MS (ESI + ): C 80 H 119 N9O7 8+ (M / Z) 164.74; UV maximum absorption wavelength: 587nm; fluorescence maximum emission wavelength: 746nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 80nM. HB-10a-2N + : Yield: 28.3%; MS (ESI + ): C 102 H 163 N 13 O7 12+ (M / Z) 140.27; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 748 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 40 nM.

[0426] Example 14a

[0427] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 280 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 0, 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55°C under nitrogen protection, and stirred in the dark for 56 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The crude product is further separated by silica gel plate chromatography to obtain black solid products HB-11a and HB-11a-N, respectively. + HB-11a-2N +HB-11a-4N + HB-11a: yield 68.2%; MS (ESI + ): C 47 H 49 N3O7 2+ (M / Z) 383.68; UV maximum absorption wavelength: 586 nm; fluorescence maximum emission wavelength: 742 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.45 μM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1): 50 ):201nM. HB-11a-N + : Yield: 46.5%; MS (ESI + ): C 55 H 67 N4O7 3+ (M / Z) 298.50; UV maximum absorption wavelength: 587 nm; fluorescence maximum emission wavelength: 743 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.45 μM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1): 50 ):154nM. HB-11a-2N + : Yield: 32.1%; MS (ESI + ): C 63 H 85 N5O7 4+ (M / Z) 255.91; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 746 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.25 μM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1): 50 ):134nM. HB-11a-4N + : Yield: 25.8%; MS (ESI + ): C 79 H 121 N7O7 6+ (M / Z) 213.32; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 750 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 100 nM; half inhibitory concentration (IC) for cholangiocarcinoma cells (HUCCT1): 50 ): 109nM.

[0428] Example 15a

[0429] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 54 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-12a-N + HB-12a-2N + HB-12a-4N + HB-12a-N + : Yield: 62.4%; MS (ESI + ): C 53 H 73 N3O9 2+ (M / Z) 447.76; UV maximum absorption wavelength: 587 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.40 μM. HB-12a-2N + : Yield: 51.0%; MS (ESI + ): C 60 H 89 N4O9 3+ (M / Z) 336.55; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 746 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.40 μM. HB-12a-4N + : Yield: 36.2%; MS (ESI + ): C 75 H 123 N6O9 5+ (M / Z) 250.39; UV maximum absorption wavelength: 592 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.15 μM.

[0430] Example 16a

[0431] The acetonitrile solution containing 100 mg of hypocrellin derivative was added dropwise to 270 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 4) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 54 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-13a-N + HB-13a-2N+ HB-13a-4N + HB-13a-N + : Yield: 52.4%; MS (ESI + ): C 46 H 59 N3O9 2+ (M / Z) 398.71; UV maximum absorption wavelength: 585nm; fluorescence maximum emission wavelength: 742nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.50μM. HB-13a-2N + : Yield: 43.0%; MS (ESI + ): C 54 H 77 N4O9 3+ (M / Z) 308.52; UV maximum absorption wavelength: 586nm; fluorescence maximum emission wavelength: 744nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.50μM. HB-13a-4N + : Yield: 36.1%; MS (ESI + ): C 70 H 113 N6O9 5+ (M / Z) 236.37; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 746 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.20 μM.

[0432] Example 17a

[0433] Containing 100mg of hypocrellin derivative, 200mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 25 hours. After the reaction was completed, the mixture was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain the crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-14a-2N + HB-14a-3N + HB-14a-2N + : Yield: 35.0%; MS (ESI + ): C 59 H 81 N5O 15 S 4+(M / Z) 282.88; UV maximum absorption wavelength: 592nm; fluorescence maximum emission wavelength: 746nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.25μM. HB-14a-3N + : Yield: 25.3%; MS (ESI + ): C 70 H 103 N7O 15 S 6+ (M / Z) 218.95; UV maximum absorption wavelength: 594 nm; fluorescence maximum emission wavelength: 747 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 95 nM.

[0434] Example 18a

[0435] Containing 100mg of hypocrellin derivatives, 200mg of cationic derivatives ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen protection for 25 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain the crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-15a-N + HB-15a-2N + HB-15a-N + : Yield: 42.2%; MS (ESI + ): C 89 H 124 N6O 18 6+ (M / Z) 260.82; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 742 nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 90 nM; half inhibitory concentration (IC 50 ):112nM. HB-15a-2N + : Yield: 33.5%; MS (ESI + ): C 117 H 180 N 10 O 18 10+ (M / Z) 201.43; UV maximum absorption wavelength: 592nm; fluorescence maximum emission wavelength: 745nm; minimum inhibitory concentration (MBC) against negative bacteria - Salmonella typhi: 60nM; half inhibitory concentration (IC 50 ): 97nM.

[0436] Example 19a

[0437] Containing 100mg of hypocrellin derivatives, 200mg of cationic derivatives ( n is the number of quaternary ammonium salt units, n = 1, 2), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 25 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain the crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-16a-N + HB-16a-2N + HB-16a-N + : Yield: 56.1%; MS (ESI + ): C 58 H 76 N5O 10 3+ (M / Z) 334.19; UV maximum absorption wavelength: 582nm; fluorescence maximum emission wavelength: 743nm; minimum inhibitory concentration (MBC) against negative bacteria - Bordetella pertussis: 0.4μM. HB-16a-2N + : Yield: 34.9%; MS (ESI + ): C 72 H 104 N7O 10 5+ (M / Z) 245.36; UV maximum absorption wavelength: 586 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Bordetella pertussis: 0.15 μM.

[0438] Example 20a

[0439] 100 mg of hypocrellin derivative, 340 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3), 60 mg of EDC-HCl and 12 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen in the dark for 32 hours. After the reaction was completed, the mixture was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-17a-2N + HB-17a-3N + HB-17a-2N + : Yield: 51.2%; MS (ESI + ): C 80 H127 N5O 12 4+ (M / Z) 337.49; UV maximum absorption wavelength: 592nm; fluorescence maximum emission wavelength: 743nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.25μM. HB-17a-3N + : Yield: 38.1%; MS (ESI + ): C 100 H 171 N7O 12 6+ (M / Z) 277.22; UV maximum absorption wavelength: 594 nm; fluorescence maximum emission wavelength: 744 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 100 nM.

[0440] Example 21a

[0441] 100 mg of hypocrellin derivative, 390 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3), 80 mg of EDC-HCl and 12 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred under nitrogen protection in the dark for 36 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-18a-2N + HB-18a-3N + HB-18a-2N + : Yield: 65.2%; MS (ESI + ): C 77 H 123 N5O 11 4+ (M / Z) 323.48; UV maximum absorption wavelength: 587nm; fluorescence maximum emission wavelength: 738nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.2μM. HB-18a-3N + : Yield: 35.1%; MS (ESI + ): C 93 H 159 N7O 11 6+ (M / Z) 258.53; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 741 nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 90 nM.

[0442] Example 22a

[0443] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 3) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55 ° C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-33a-N + HB-33a-2N + HB-33a-3N + HB-33a-N + : Yield: 65.5%; MS (ESI + ): C 55 H 73 N4O8 3+ (M / Z) 305.85; UV maximum absorption wavelength: 586nm; fluorescence maximum emission wavelength: 745nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.30μM. HB-33a-2N + : Yield: 52.0%; MS (ESI + ): C 63 H 91 N5O8 4+ (M / Z) 261.42; UV maximum absorption wavelength: 587nm; fluorescence maximum emission wavelength: 746nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.65μM. HB-33a-3N + : Yield: 48.3%; MS (ESI + ): C 71 H 109 N6O8 5+ (M / Z) 234.77; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 748 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.30 μM.

[0444] Example 23a

[0445] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( (n is the number of quaternary ammonium salt units, n = 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 32 hours. After the reaction was completed, the mixture was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-34a-2N + HB-34a-3N + HB-34a-2N + : Yield: 52.1%; MS (ESI + ): C 53 H 75 N3O9 2+ (M / Z) 448.77; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 744 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 2.50 μM. HB-34a-3N + : Yield: 39.3%; MS (ESI + ): C 61 H 93 N4O9 3+ (M / Z) 341.90; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 745 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.40 μM.

[0446] Example 24a

[0447] 100 mg of the acetonitrile solution of the hypocrellin derivative was added dropwise to 300 mg of the cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3) in a mixed solution of acetonitrile: dimethyl sulfoxide (V = 3:1), heated to 55°C under nitrogen protection, and stirred in the dark for 48 hours. After the reaction is completed, the reaction system is distilled under reduced pressure to remove acetonitrile, and the mixture solution is extracted with H2O and DCM. The aqueous phase is collected and freeze-dried to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography to obtain black solid products HB-35a-2N + HB-35a-3N + HB-35a-2N + : Yield: 46.1%; MS (ESI + ): C 54 H 81 N4O8 3+(M / Z) 304.54; UV maximum absorption wavelength: 586 nm; fluorescence maximum emission wavelength: 742 nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 1.45 μM; half inhibitory concentration (IC 50 ):108nM. HB-35a-3N + : Yield: 36.5%; MS (ESI + ): C 64 H 103 N5O8 4+ (M / Z) 267.44; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 744 nm; minimum inhibitory concentration (MBC) for negative bacteria - Pseudomonas aeruginosa: 0.70 μM; half inhibitory concentration (IC 50 ): 95nM.

[0448] Example 25a

[0449] 100 mg of hypocrellin derivative acetonitrile solution was added dropwise to 300 mg of cationic derivative A mixture of acetonitrile and dimethyl sulfoxide (V=3:1) was heated to 55°C under nitrogen and stirred in the dark for 48 hours. After completion of the reaction, the acetonitrile was removed by distillation under reduced pressure, and the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain the black solid product HB-36a. HB-36a: Yield 36.5%; MS (ESI + ): C 54 H 80 N6O7 4+ (M / Z) 231.15; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 742 nm; minimum inhibitory concentration (MBC) against negative bacteria - Pseudomonas aeruginosa: 0.65 μM; half inhibitory concentration (IC 50 ): 101nM.

[0450] Example 26a

[0451] 100mg of hypocrellin derivatives, 360mg of cationic derivatives 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide (DMSO) solution, thoroughly mixed, and stirred under nitrogen in the dark for 32 hours. After completion, the mixture was extracted with H2O and DCM. The aqueous phase was collected and freeze-dried to obtain the crude product. The crude product was further separated by silica gel chromatography to obtain HB-37a, a black solid. HB-37a: Yield 39.2%; MS (ESI + ): C 66 H 97 N6O 13 5+ (M / Z) 236.34; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 735 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.35 μM.

[0452] Example 27a

[0453] 100 mg of hypocrellin derivative, 390 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 1, 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 38 hours. After the reaction was completed, the mixture solution was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-38a-N + HB-38a-2N + HB-38a-3N + HB-38a-N + : Yield: 79.2%; MS (ESI + ): C 56 H 69 N3O 10 2+ (M / Z) 471.75; UV maximum absorption wavelength: 586nm; fluorescence maximum emission wavelength: 736nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 2.35μM. HB-38a-2N + : Yield: 61.2%; MS (ESI + ): C 64 H 87 N4O 10 3+ (M / Z) 357.21; UV maximum absorption wavelength: 588 nm; fluorescence maximum emission wavelength: 738 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.30 μM. HB-38a-3N + : Yield: 31.6%; MS (ESI+ ): C 72 H 105 N5O 10 4+ (M / Z) 299.95; UV maximum absorption wavelength: 589 nm; fluorescence maximum emission wavelength: 742 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 0.65 μM.

[0454] Example 28a

[0455] 100 mg of hypocrellin derivative, 360 mg of cationic derivative ( n is the number of quaternary ammonium salt units, n = 2, 3), 40 mg of EDC-HCl and 6.1 mg of DMAP were dissolved in dimethyl sulfoxide solution, mixed thoroughly, and stirred in the dark under nitrogen for 32 hours. After the reaction was completed, the mixture was extracted with H2O and DCM, the aqueous phase was collected, and freeze-dried to obtain a crude product. The crude product was further separated by silica gel plate chromatography to obtain black solid products HB-39a-2N + HB-39a-3N + HB-39a-2N + : Yield: 58.3%; MS (ESI + ): C 56 H 79 N3O9 2+ (M / Z) 468.79; UV maximum absorption wavelength: 587 nm; fluorescence maximum emission wavelength: 729 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 2.40 μM; half inhibitory concentration (IC 50 ):140nM. HB-39a-3N + : Yield: 43.6%; MS (ESI + ): C 66 H 101 N4O9 3+ (M / Z) 364.59; UV maximum absorption wavelength: 590 nm; fluorescence maximum emission wavelength: 735 nm; minimum inhibitory concentration (MBC) against negative bacteria - Escherichia coli: 1.35 μM; half inhibitory concentration (IC50) against skin squamous cell carcinoma cells (A431): 50 ): 102nM.

[0456] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A hypocrellin derivative or an isomer thereof represented by formula (1), formula (2), or formula (1A): In formula (1) or (2), R1 is H or COCH3; C 13 、C 14 and C 15 The dotted line indicates that the double bond is located at C 13 =C 14 or C 14 =C 15 , and C 13 、C 14 and C 15 There is only one double bond between In formula (1), the dotted line of T1 indicates that R4 and R5 are connected or not connected. When R4 and R5 are connected, they, together with the C at the 2' and 3' positions, form the following group which is unsubstituted or substituted by one, two or more Ra: C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; wherein T1 is unsubstituted or substituted C3-C 12 A linker obtained by removing the 2' and 3' carbon atoms from a cycloalkyl or 3-12 membered heterocyclic group; Ra is selected from R, C1-C 12 Alkyl, C1-C 12 Alkoxy, hydroxy, thiol, carboxyl, amino or sulfonic acid groups; When R4 and R5 are not connected, R3, R4, R5 and R6 are the same or different and are independently selected from H, R, Cl-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, oxa C2-C 12 Alkyl, hydroxyl, mercapto, carboxyl, sulfonic acid or glycol acetal groups; R2 and R7 are the same or different and are independently selected from H, C1-C 12 Alkyl, C1-C 12 Alkoxy, halogenated C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C6-C 12 Aryl, -C1-C 12 Alkyl-C6-C 12 Aryl, 3-12 membered heterocyclic group, hydroxyl, thiol, carboxyl, sulfonic acid, oxaC2-C 10 Alkyl or glycol group; the -C1-C 12 Alkyl-C6-C 12 The aryl group of the aryl group is optionally substituted by one, two or more Rb, Rb is selected from the following groups: C1-C 12 Alkyl, C1-C 12 Alkoxy or -C1-C 12 Alkyl-N + (C1-C 12 alkyl)3; In formula (2), the dotted line of T2 represents two adjacent R8 and R9, R 10 With R 11 Connected or not connected; when two adjacent R8 and R9, or R 10 and R 11 When not connected, R8 and R 11 OH, R9 and R 10 is H; When two adjacent R8 and R9 are linked together, R8 and R9, together with T2 and positions 4 and 5, form a saturated or unsaturated six-membered heterocyclic ring substituted or unsubstituted by one, two or more Rc, wherein T2 is a linker between R8 and R9; When two adjacent R 10 With R 11 When connected, R 10 and R 11 Together with T2 and positions 8 and 9, it forms a saturated or unsaturated six-membered heterocyclic ring substituted or unsubstituted by one, two or more Rc, wherein T2 is R 10 and R 11 The connector between Rc is selected from C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, carboxyl, -COO-C1-C 12 Alkyl, -CONH-C1-C 12 Alkyl, oxaC2-C 12 Alkyl, R, aldehyde, hydroxyl, thiol, carboxyl, sulfonic acid, glycol acetal, C3-C 12 Cycloalkyl, C6-C 12 Aryl or 3-12 membered heterocyclic group; In formula (1) or (2), R is the same or different, and its structure is shown in formula (3): In formula (3), t and u are independently selected from integers from 0 to 15, r is 0 or 1, and s is 0 or 1; v are the same or different and are independently selected from integers from 0 to 6; In formula (3), the linking groups X and Y are the same or different and are independently -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -C(=O)-, -CH=CH-, -C≡C-, -SO3-, -N + (R 20 )(R 21 )-、-NHCO-C3-C 12 Cycloalkyl-; unsubstituted or optionally substituted by Rk: -C3-C 12 Cycloalkenyl-, -C3-C 12 Cycloalkyl-, -C6-C 12 Aryl-, -3-12 membered heterocyclic-; said Rk is selected from C1-C 12 Alkyl, carboxyl, amino, hydroxyl, -COOC1-C 12 Alkyl or -C1-C 12 Alkyl-COOH; In formula (3), J and K are the same or different and are independently a quaternary ammonium salt cation, and the general structural formula thereof is shown in (4-1) or (4-2): In formula (4-1), E is N or P; In formulas (4-1) and (4-2), m, m1, n, and n1 are independently selected from integers from 0 to 15, and p and q are independently selected from integers from 0 to 12; provided that: When J is selected from formula (4-1) and K is selected from formula (4-2), p and q are not 0 at the same time; or, When K is selected from formula (4-1) and J is selected from formula (4-2), p and q are not 0 at the same time; or, When J and K are both selected from formula (4-1), the two ps are not 0 at the same time; or, When J and K are selected from formula (4-2) at the same time, the two qs are not 0 at the same time; In formula (3), the terminal group Z is selected from hydrogen, hydroxyl, carboxyl, amino, thiol, sulfonic acid, C1-C 12 Alkyl, C1-C 12 Alkoxy, -COOC1-C 12 Alkyl, oxaC2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; j = 1-60 (e.g. 1-30); C6-C ... 12 Aryl; unsubstituted or substituted with one, two or more Rf pyridinium salts -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ); Rd, Re, and Rf are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C 12 Alkyl, C1-C 12 Alkyl, -C1-C 12 Alkyl-OH, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 6-12 membered aryl; or one, two or more hydroxyl, carboxyl, sulfonic acid or -COOC1-C 12 Alkyl-substituted C1-C 12 alkyl; R 12 、R 13 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 The same or different, each independently being unsubstituted or optionally substituted by one, two or more Rg: C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 12 Aryl, C6-C 12 Aryl-C1-C 12 Alkyl-, oxaC2-C 12 Alkyl, aza C2-C 12 Alkyl or thia C2-C 12 alkyl; Rg is selected from hydroxyl, carboxyl, sulfonic acid or carboxylate groups (-COOC1-C 12 alkyl); In formula (1) or formula (2), the anion paired with the cation in group R is any pharmaceutically acceptable anion; In formula (1A), R 1a is H or COCH3; C 13 、C 14 and C 15 The dotted line indicates that the double bond is located at C 13 =C 14 or C 14 =C 15 , and C 13 、C 14 and C 15 There is only one double bond between R 2a Selected from -NH-C1-C 12 Alkyl, -NH-C3-C 12 Cycloalkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl, -NH-(O hetero C2-C 12 Alkyl), -NH-(CH2CH2O) j -CH3, j = 1-60, -NH-C1-C 12 Alkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-COOH, -NH-(O hetero C2-C 12 Alkyl)-R', -NH-(O and N hetero C4-C 12 Alkyl), -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl-C1-C 12 Alkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-OH, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-R', -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-R', -NH-(O and N hetero C4-C 12 alkyl)-R'; R 3a and R 4a The same or different, independently selected from R', OH, -NH-C1-C 12 Alkyl, -NH-C3-C 12 Cycloalkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl, -NH-(O hetero C2-C 12 Alkyl), -O-C1-C 12 Alkyl-R', -NH-C1-C 12 Alkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl, -NH-C1-C 12 Alkyl-C6-C 12 Aryl-C1-C 12 Alkyl, -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-OH, -NH-(O hetero C2-C 12 Alkyl)-R', -NH-C1-C 12 Alkyl-C3-C 12 Cycloalkyl-R', -NH-C1-C 12 Alkyl-C6-C 12 Aryl-R', -NH-(O and N hetero C4-C 12 alkyl)-R'; R 5a Selected from R' or methyl; The condition is R 2a 、R 5a At least one group is R' or a substituent containing R'; The structure of R' is shown in formula (3A): In formula (3A), J' and K' are the same or different and are independently a quaternary ammonium salt cation, and the general structure thereof is shown in (4-1A) or (4-2A): In formula (4-1A), E is N or P; In formulas (4-1A) and (4-2A), m, m1, n, and n1 are independently selected from integers of 0 to 15, and p' and q' are independently selected from integers of 0 to 12; In formula (3A), t' and u' are independently selected from integers of 0 to 15; r' is 0 or 1, s' is 0 or 1; v' is selected from integers of 0 to 6; The linking groups X' and Y' are the same or different and are each independently -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -C(=O)-, -CH=CH-, -C≡C-, -SO3-, -N + (R 20 )(R 21 )-、-NHCO-C3-C 12 Cycloalkyl-, unsubstituted or optionally substituted by Rk': -C3-C 12 Cycloalkenyl-, -C3-C 12 Cycloalkyl-, -C6-C 12 Aryl-, -3-12 membered heterocyclic-; said Rk' is selected from C1-C 12 Alkyl, carboxyl, amino, hydroxyl, -COOC1-C 12 Alkyl or -C1-C 12 Alkyl-COOH; The terminal group Z' is selected from hydrogen, hydroxyl, carboxyl, amino, mercapto, sulfonic acid (-SO3H), C1-C 12 Alkyl, C1-C 12 Alkoxy, -COOC1-C 12 Alkyl, oxaC2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd' C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; j = 1-60 (eg 1-30); C6-C substituted with one, two or more Re' 12 Aryl; unsubstituted or substituted by one, two or more Rf' substituted pyridinium salt, -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ); Rd', Re', Rf' are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C 12 Alkyl, C1-C 12 Alkyl, -C1-C 12 Alkyl-OH, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 6-12 membered aryl; or one, two or more hydroxyl, carboxyl, sulfonic acid or -COOC1-C 12 Alkyl-substituted C1-C 12 alkyl; R 12 、R 13 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 The same or different, each independently being unsubstituted or optionally substituted by one, two or more Rg: C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 12 Aryl, C6-C 12 Aryl-C1-C 12 Alkyl-, oxaC2-C 12 Alkyl, aza C2-C 12 Alkyl or thia C2-C 12 alkyl; Rg is selected from hydroxyl, carboxyl, sulfonic acid or -COOC1-C 12 alkyl; Furthermore, formula (3A) contains at least two groups with cations; In formula (1A), the anion paired with the cation in group R' is any pharmaceutically acceptable anion.

2. The hypocrellin derivative or isomer thereof according to claim 1, characterized in that The isomers are enol tautomers; Alternatively, in formula (3) or formula (3A), t, u, t', u' are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; v, v' are independently selected from 0, 1, 2, 3 or 4; Alternatively, X and Y in formula (3) are the same or different, or X' and Y' in formula (3A) are the same or different, and are each independently selected from -NH-, -C=N-, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO-, -SO3-, -N + (R 20 )(R 21 )-, -NHCO-C3-C6 cycloalkyl-; Alternatively, the terminal group Z in formula (3) or the terminal group Z' in formula (3A) is selected from hydrogen, hydroxyl, carboxyl, amino, thiol, sulfonic acid, C1-C6 alkyl, C1-C6 alkoxy, -COOC1-C6 alkyl, oxa-C2-C 12 Alkyl; unsubstituted or substituted by one, two or more Rd C3-C6 cycloalkyl or 3-6 membered heterocyclic group; j = 1-10; phenyl which is unsubstituted or substituted by one, two or more Re; pyridinium salt which is unsubstituted or substituted by one, two or more Rf, -N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ); where R 22 、R 23 、R 24 、R 25 、R 26 、R 27 are the same or different and are independently C1-C6 alkyl or phenyl; Rd, Re, and Rf are the same or different and are independently selected from hydroxyl, carboxyl, sulfonic acid, -COOC1-C6 alkyl, C1-C6 alkyl, or -C1-C6 alkyl-OH; Or, R 12 、R 13 、R 20 、R 21 are the same or different and are each independently C1-C6 alkyl, oxa-C2-C6 alkyl, aza-C2-C6 alkyl or thia-C2-C6 alkyl; Alternatively, in formula (4-1), formula (4-2), formula (4-1A) or formula (4-2A), m, m1, n, n1 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p, q, p', q' are independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; Alternatively, in formula (1A), R 3a and R 4a Selected from -OH; Alternatively, in formula (1A), the R 2a Selected from -NH-C1-C6 alkyl, -NH-C3-C6 cycloalkyl, -NH-C1-C6 alkyl-C3-C6 cycloalkyl, -NH-(O hetero C2-C6 alkyl), -NH-C1-C6 alkyl-R', -NH-C1-C6 alkyl-phenyl, -NH-C1-C6 alkyl-C3-C6 cycloalkyl-COOH, -NH-(O hetero C2-C6 alkyl)-R', -NH-(O and N hetero C4-C6 alkyl), -NH-C1-C6 alkyl-C3-C6 cycloalkyl-R', -NH-C1-C6 alkyl-phenyl-C 1-6 Alkyl, -NH-C1-C6 alkyl-C3-C6 cycloalkyl-OH, -NH-C1-C6 alkyl-phenyl-R', -NH-C1-C6 alkyl-C3-C6 cycloalkyl-R', -NH-(O and N hetero C4-C6 alkyl)-R'; Alternatively, in formula (1A), the group with a cation is selected from Pyridinium salts, unsubstituted or substituted by one, two or more Rf', -N + (R 20 )(R 21 )-、-N + (R 22 )(R 23 )(R 24 ) or -P + (R 25 )(R 26 )(R 27 ).

3. The hypocrellin derivative or isomer thereof according to claim 1 or 2, characterized in that In formula (1), when R4 and R5 are not connected, R3, R4, R5 and R6 are the same or different and are independently selected from H, C1-C6 alkyl, -halo-C1-C6 alkyl, C1-C6 alkoxy or oxa-C2-C 10 alkyl; Alternatively, in formula (1), when R4 and R5 are connected, R4, R5 and T1 form the following ring system which is substituted by one or two Ra or is unsubstituted: a five-membered ring, a six-membered ring or a seven-membered ring, the structure of which is shown in formula (4), wherein Ring A is a saturated or unsaturated five-membered, six-membered, or seven-membered heterocyclic group; or a five-membered, six-membered, or seven-membered cycloalkyl group; Ra is selected from C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkyl; Alternatively, in formula (1), R2 and R7 are the same or different and are independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, -C1-C6 alkyl-phenyl, 3-6 membered heterocyclic group, hydroxyl, thiol, carboxyl, sulfonic acid, glycol acetal or oxa-C2-C 10 Alkyl; the phenyl group in the -C1-C6 alkyl-phenyl group is optionally substituted by one, two or more Rb, Rb being selected from the following groups: C1-C 10 Alkyl, C1-C6 alkoxy or -C1-C 10 Alkyl-N + (C1-C6 alkyl)3; Alternatively, in formula (3), formula (3A), formula (4-1), formula (4-2), formula (4-1A) and formula (4-2), m, m1, n, n1, t, u, t', u' are independently selected from 0, 1, 2, 3, 4, 5 or 6; v or v' is selected from 0, 1 or 2; p, q, p', q' are independently selected from 0, 1, 2, 3, 4, 5 or 6; Alternatively, in formula (2), when R8 and R9 are not connected, R8 is OH and R9 is H; Or, in formula (2), when R 10 and R 11 When not connected, R 11 OH, R 10 For H.

4. The hypocrellin derivative or isomer thereof according to any one of claims 1 to 3, characterized in that Formula (3) is shown as follows (5-1) or (5-2): Among them, v, X, Y, r, m, m1, n, n1, R 12 、R 13 , q, p, s, u, t, Z have the definitions in any one of claims 1 to 3; in (5-1) or (5-2), p and q are not 0 at the same time; Alternatively, the formula (3A) is the structure shown in (5-1A) or (5-2A): Among them, v', X', Y', r', m, m1, n, n1, R 12 、R 13 , q', p', s', u', t', Z' have the definitions described in any one of claims 1-3; Formula (5-1A) or (5-2A) contains at least two groups with cations.

5. The hypocrellin derivative or isomer thereof according to any one of claims 1 to 4, characterized in that In formula (3) or formula (3A), X and Y are the same or different, and X' and Y' are the same or different, and are each independently -N + (CH3)2-, -C=N-, -NH-, -O-, -S-, -COO-, -OCO-, -SO3-, -CONH-, -NHCO-, -NHCO-cyclopropyl-, -NHCO-cyclobutyl-, -NHCO-cyclopentyl-, -NHCO-cyclohexyl-, -C(=O)-, -CH=CH-, -C≡C-, -cyclopropyl-, -cyclobutyl-, -cyclopentyl-, -C5H7(CH3)-<methylcyclopentylidene>, -C5H7(OH)-<hydroxycyclopentylidene>, -C5H7(NH2)-<aminocyclopentylidene>, -C6H 10 -<cyclohexylene>, -C6H9(CH3)-<methylcyclohexylene>, -C6H9(C2H5)-<ethylcyclohexylene>, -C6H9(C3H7)-<propylcyclohexylene>, -C6H9(C4H9)-<butylcyclohexylene>, -C6H8(CH3)2-<dimethylcyclohexylene>, -C6H9(OH)-<hydroxycyclohexylene>, -C6H9(NH2)-<aminocyclohexylene>, -C6H9(COOH)-<carboxycyclohexylene>, -C6H9(CH2COOH)-<carboxymethylcyclohexylene>, -C6H9(C2H5COOH)-<carboxyethylcyclohexylene>, -cycloheptyl-, -phenyl-, -pyridyl-, -C5H2N(CH3)-<methylpyridylene>, Alternatively, the terminal group Z in formula (3) or the terminal group Z' in formula (3A) is selected from: -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 、-C6H 13 , -C6H5, -C5H4N, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 、-OC6H 13 、-OH、-NH2、-SH、-COOH、-COOCH3、-COOC2H5、-SO3H、cycloalkyl、 j＝1-6； Alternatively, in formula (1), R2 and R7 are the same or different and are independently selected from H, -C1-C6 alkyl-phenyl, -C1-C6 alkyl-phenyl-C1-C 10 Alkyl-N + (C1-C6 alkyl)3, -C1-C6 alkyl-phenyl-C1-C 10 Alkyl, oxaC2-C 10 alkyl; Alternatively, the anion paired with the cation in formula (1) or (1A) is a halide ion, a sulfate ion, a phosphate ion, or a sulfonate ion.

6. The hypocrellin derivative or isomer thereof according to any one of claims 1 to 5, characterized in that The hypocrellin derivatives are selected from the following compounds:

7. The hypocrellin derivative or isomer thereof according to any one of claims 1 to 6, characterized in that The isomer of formula (1) is the enol tautomer shown in formula (1'); or, the isomer of formula (2) is the enol tautomer shown in formula (2'); the isomer of formula (1A) is the enol tautomer shown in formula (1A'): Wherein, each group and dotted line has the definition as described in any one of claims 1-6.

8. Use of the hypocrellin derivative or its isomer according to any one of claims 1 to 7 in the preparation of photodynamic therapy drugs.

9. The use according to claim 8, characterized in that The photodynamic therapy drug is a photosensitizer drug; the photosensitizer drug is used to treat cancer; the cancer is, for example, cervical cancer, skin squamous cell carcinoma, esophageal cancer or bile duct cancer.

10. The use according to claim 8, characterized in that The photodynamic therapy drug is a photosensitizer drug, which is used for inhibiting or killing bacteria, for example, for inhibiting or killing Gram-negative bacteria, Gram-positive bacteria or fungi; Preferably, the photosensitizer drug is used to inhibit or kill the following bacteria: Escherichia coli, Pseudomonas aeruginosa, Proteus, Salmonella typhi, Bordetella pertussis, Salmonella, Klebsiella, Neisseria meningitidis, Staphylococcus aureus; or to inhibit or kill the following fungi: Candida albicans, Mucor.

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