A thionaphthimide organic antibacterial photosensitizer, a preparation method and application thereof

Abstract

The application provides a thionaphthimidyl organic antibacterial photosensitizer, a preparation method and application thereof, and belongs to the field of photosensitizers and antibacterial photodynamic therapy; the thionaphthimidyl compound has the following general formula: The thionaphthimidyl organic antibacterial photosensitizer provided by the application has high efficient photodynamic properties and bacterial targeting ability; the photosensitizer has high photosensitization ability and high singlet oxygen yield, and can be specifically enriched on the surface of bacteria (such as MRSA and VISA), and a large amount of active oxygen is generated under light, so that the bacteria can be efficiently killed. The photosensitizer has no obvious toxicity to normal cells at an effective treatment concentration, and has a strong application prospect in antibacterial photodynamic therapy.

Description

Technical Field

[0001] This invention relates to the field of photosensitizer technology, specifically to a thionaphthalene imide-based organic antibacterial photosensitizer, its preparation method, and its application. Background Technology

[0002] Photodynamic sterilization is a novel non-thermal sterilization technology. Its principle is as follows: under irradiation with excitation light of a specific wavelength, a photosensitizer (PS) absorbs photon energy and is excited to a triplet state. This excitation then generates reactive oxygen species (ROS), such as singlet oxygen and superoxide anions, through type I or type II reactions. These ROS cause oxidative damage to biomolecules such as lipids, proteins, and nucleic acids within pathogens, disrupting their structural or functional integrity, thereby leading to the death of the pathogenic microorganisms. Because this mechanism has multiple targets and is less likely to induce bacterial resistance, this technology is considered a promising alternative strategy to address the antibiotic resistance crisis.

[0003] Despite the significant advantages of photodynamic antibacterial technology, its practical application effectiveness is highly dependent on the performance of the photosensitizer itself. Currently, while common photosensitizers (such as porphyrins and phenothiazines) exhibit good photodynamic bactericidal activity, their bactericidal efficiency still falls short of the requirements for highly effective treatment of drug-resistant bacteria. Furthermore, many photosensitizers, while exerting their bactericidal effects, inevitably exhibit varying degrees of toxicity to normal mammalian cells, significantly limiting the application of this technology in clinical anti-infection treatment. Therefore, developing novel photosensitizers that combine highly efficient reactive oxygen species generation with good biocompatibility has become an important and urgent task in this field. Summary of the Invention

[0004] In view of this, the present invention provides a thionaphthalene imide-based organic antibacterial photosensitizer, its preparation method, and its application. The thionaphthalene imide-based organic antibacterial photosensitizer or its pharmaceutically acceptable salt provided by the present invention possesses highly efficient reactive oxygen species generation capacity, excellent antibacterial activity, and good biocompatibility, demonstrating significant application potential in the field of photodynamic antibacterial agents.

[0005] The technical solution of the present invention is as follows: A thionaphthalene imide organic antibacterial photosensitizer or a pharmaceutically acceptable salt thereof, having the structure shown in general formula (I): General Formula (I) R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1 groups. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy, substituted or unsubstituted C1 C3 alkylthio group, substituted or unsubstituted amino group, substituted or unsubstituted amide group, substituted or unsubstituted acyloxy group; p represents the number of R1 substituents on the benzene ring, and p is any integer from 0 to 6; R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted amino groups, and substituted or unsubstituted C1 groups, respectively. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy group; X, Y, and Z are each independently selected from oxygen or sulfur; L is selected from substituted or unsubstituted aniline, substituted or unsubstituted benzylamine, five-membered heterocyclic amine, six-membered heterocyclic amine, C3-C8 alkylamine, and C3-C8 cycloalkylamine. Indicates the connection site.

[0006] In some embodiments, R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy, substituted or unsubstituted C1 C3 alkylthio group, substituted or unsubstituted amino group, substituted or unsubstituted amide group, substituted or unsubstituted acyloxy group; p is 0 or 1; R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, and C1 groups, respectively. C3 alkyl-substituted or unsubstituted amino groups, substituted or unsubstituted C1 C3 alkyl, substituted or unsubstituted C1 C3 alkoxy group; L is selected from cyclohexylamine, aniline, benzylamine, oxygen- or nitrogen-containing five-membered heterocyclic amines, oxygen- or nitrogen-containing six-membered heterocyclic amines, or C3-C8 imideamine groups; In some of these embodiments, R1 is independently selected from hydrogen or dimethylamino; R2, R3, and R4 are independently selected from hydrogen, halogen, and methyl, respectively; X, Y, and Z are each independently selected from oxygen or sulfur; L is selected from one of the following groups: , or .

[0007] In some embodiments, the thionaphthalene imide compound or a pharmaceutically acceptable salt thereof has any of the following structures: , , , , , , , , , , .

[0008] This invention also provides a method for preparing the above-mentioned thionaphthalene imide photosensitizer or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) Compound B1 and compound NH2-L were reacted via an aminolysis reaction to prepare intermediate compound B2; (b) The intermediate compound B2 is subjected to a condensation reaction to prepare intermediate compound B3; (c) The carbonyl group of the intermediate compound B3 is subjected to a thioreaction to prepare the compound; The structural formula of compound B1 includes ; The structural formula of the intermediate compound B2 includes: ; The structural formula of the intermediate compound B3 includes .

[0009] In some embodiments, the intermediate compound B2 undergoes a condensation reaction with a carboxylic acid compound or an acyl chloride compound; The carboxylic acid compound or acyl chloride compound includes one of the following structural formulas: or .

[0010] The definitions of R1, R2, R3, R4, L, and p are the same as those described above.

[0011] The present invention also provides thionaphthalene imide photosensitizers as described above or pharmaceutically acceptable salts thereof, or thionaphthalene imide compounds or pharmaceutically acceptable salts thereof prepared according to the above preparation method.

[0012] The present invention also provides the application of the above-mentioned thionaphthalene imide compound in antibacterial photodynamic therapy.

[0013] And the application of the aforementioned thionaphthalene imide organic antibacterial photosensitizers or their pharmaceutically acceptable salts in the preparation of reagents that selectively kill bacteria in bacteria and normal mammalian cells.

[0014] The bacteria are one or more of the following: Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, Enterococcus faecalis, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter baumannii. The normal cells are mouse fibroblast L929 cells and mouse erythrocytes.

[0015] The beneficial effects of this invention are as follows: (1) This invention constructs a photosensitizer based on a thionaphthaleneimide skeleton. By introducing sulfur atoms, it effectively promotes the intersystem crossing process of molecules, significantly improving its reactive oxygen species generation efficiency, thereby endowing it with excellent photodynamic antibacterial properties. In addition, the photosensitizer is a novel structural compound reported for the first time. Its preparation method has the advantages of simple preparation process and readily available raw materials, and has good industrialization prospects and application potential.

[0016] (2) The thionaphthalene imide organic antibacterial photosensitizer provided by the present invention can be activated to generate singlet oxygen under light irradiation, and the generation rate is faster than that of commercial dye RB.

[0017] (3) The thionaphthalene imide organic antibacterial photosensitizer provided by the present invention can selectively produce strong phototoxicity to bacteria, and has excellent therapeutic effect and good biological safety.

[0018] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Attached Figure Description

[0019] To make the objectives, technical solutions, and advantages of the present invention clearer, the preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein: Figure 1 (a) Normalized UV-Vis absorption spectra of compound K9 in different polar solvents; (b) Fluorescence emission spectra of compound K9 (10 μM) and its sulfurized precursor compound 3-f (10 μM) in toluene solution.

[0020] Figure 2 (a) Response curve of singlet oxygen indicator DPBF to reactive oxygen species generated by commercial dye Rose Bengal (10 μM). Under green light irradiation, the UV-Vis absorption intensity of indicator DPBF decreases significantly with increasing time; (b) Response curve of singlet oxygen indicator DPBF to reactive oxygen species generated by compound K9 (10 μM). Under the same conditions, the UV-Vis absorption intensity of indicator DPBF decreases with increasing time; (c) Scatter plots of the absorption intensity of indicator DPBF at 416 nm versus irradiation time in Figures a and b.

[0021] Figure 3(a) EPR characterization of the hydroxyl radical of compound K9 under both illuminated and non-illuminated conditions; (b) Time response curve of superoxide anion indicator DHR123 to photosensitizer K9 (5 μM). Test conditions: emission wavelength of 526 nm under green light irradiation.

[0022] Figure 4 The levels of reactive oxygen species induced by different treatments after co-incubation of compound K9 (10 μM) with methicillin-resistant Staphylococcus aureus (Note: The data in the figure are statistical results of DCFH-DA fluorescence intensity).

[0023] Figure 5 Effect of compound K9 concentration on its photodynamic antibacterial effect. (a) Colony plate images of methicillin-resistant Staphylococcus aureus treated with different concentrations of K9; (b) Survival statistics based on plate colony counts.

[0024] Figure 6 Effect of pre-incubation time on the photodynamic antibacterial effect of compound K9 (0.025 μg / mL). (a) Colony plate images of methicillin-resistant Staphylococcus aureus under different pretreatment times; (b) Survival statistics based on plate colony counts.

[0025] Figure 7 Effect of light exposure time on the photodynamic antibacterial effect of K9 (0.025 μg / mL). (a) Photographs of methicillin-resistant Staphylococcus aureus (MRSA) colonies after different green light irradiation times; (b) Survival statistics based on plate colony counts.

[0026] Figure 8 (a) Images of hemolysis after co-incubation of red blood cells with different concentrations of K9; (b) Statistical graph of hemolysis rate.

[0027] Figure 9 Survival rate of L929 fibroblasts after different treatments with different concentrations of compound K9. Detailed Implementation

[0028] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that the illustrations provided in the following embodiments are only schematic representations of the basic concept of the present invention. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0029] The accompanying drawings are for illustrative purposes only and represent schematic diagrams, not actual physical images. They should not be construed as limiting the invention. To better illustrate the embodiments of the invention, some components in the drawings may be omitted, enlarged, or reduced, and do not represent the actual dimensions of the product. It is understandable that some well-known structures and their descriptions may be omitted in the drawings for those skilled in the art. The terms used in the accompanying drawings to describe positional relationships (such as "upper," "lower," "left," "right," "front," and "rear") are for illustrative purposes only and should not be construed as limiting the invention. Those skilled in the art can understand the specific meaning of these terms according to the specific circumstances.

[0030] In this invention, terms such as "further," "even more," and "particularly" are used for descriptive purposes and to indicate differences in content, but should not be construed as limiting the scope of protection of this invention.

[0031] In this invention, "A and B are independently selected from x, y or z" means that A and B are independent events, and event A does not affect the occurrence of event B. Therefore, when A is selected from x, B can be selected from any one of x, y or z; when A is selected from y, B can be selected from any one of x, y or z; when A is selected from z, B can be selected from any one of x, y or z.

[0032] In this invention, "alkyl" can refer to a straight-chain, branched, and / or cyclic alkyl group. The number of carbon atoms in an alkyl group can be 1 to 50, 1 to 30, 1 to 20, 1 to 10, or 1 to 6. Phrases containing this term, such as "C1-C9 alkyl," refer to alkyl groups containing 1 to 9 carbon atoms, and each time it appears, it can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, or C9 alkyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-octyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, 1,1-dimethylbutyl, adamantane, etc.

[0033] The term "cycloalkyl" refers to a cyclic organic group containing only carbon and hydrogen atoms, preferably 3 to 10 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

[0034] The term "alkoxy" refers to a group having an -O-alkyl group, i.e., an alkyl group as defined above that is attached to a parent nucleus via an oxygen atom. Suitable examples of phrases containing this term include, but are not limited to: methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2-CH3 or -OEt), and tert-butoxy (-OC(CH3)3 or -OtBu). The term "alkathio" includes branched and straight-chain alkyl groups attached to a bridging sulfur atom, such as methylthio.

[0035] In this invention, "heterocyclic group" and "heterocycle" have the same meaning and can be used interchangeably. The term "heterocyclic group" refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom. The non-carbon atom can be a nitrogen atom, an oxygen atom, a sulfur atom, etc., representing nitrogen-containing heterocycles, oxygen-containing heterocycles, and sulfur-containing heterocycles, respectively. It can be a saturated ring or a partially unsaturated ring. Specifically, a "five-membered heterocyclic group" refers to a group formed by a cyclic organic compound composed of carbon atoms and non-carbon atoms, where the sum of the number of carbon atoms and the number of non-carbon atoms is 5. A "six-membered heterocyclic group" refers to a group formed by a cyclic organic compound composed of carbon atoms and non-carbon atoms, where the sum of the number of carbon atoms and the number of non-carbon atoms is 6.

[0036] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0037] In this invention, the single bond connecting the substituents penetrates the corresponding ring, indicating that the substituent can be optionally attached to any ring. Location connection, for example R can be attached to any substituted site on the naphthalene ring.

[0038] This invention provides a thionaphthalene imide-based organic antibacterial photosensitizer or a pharmaceutically acceptable salt thereof, having the structure shown in general formula (I): General Formula (I) R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1 groups. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy, substituted or unsubstituted C1 C3 alkylthio group, substituted or unsubstituted amino group, substituted or unsubstituted amide group, substituted or unsubstituted acyloxy group; p represents the number of R1 substituents on the benzene ring, and p is any integer from 0 to 6; R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted amino groups, and substituted or unsubstituted C1 groups, respectively. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy group; X, Y, and Z are each independently selected from oxygen or sulfur; L is selected from substituted or unsubstituted aniline, substituted or unsubstituted benzylamine, five-membered heterocyclic amine, six-membered heterocyclic amine, C3-C8 alkylamine, and C3-C8 cycloalkylamine. Indicates the connection site.

[0039] The thionaphthaleneimide-based organic antibacterial photosensitizer provided by this invention has a simple structure and combines highly efficient photodynamic activity with bacterial targeting ability. It exhibits strong photosensitization ability, high singlet oxygen production, and can specifically accumulate on the surface of bacteria (such as MRSA and VISA), generating a large amount of reactive oxygen species under light irradiation, thereby efficiently killing bacteria. This photosensitizer shows no significant toxicity to normal cells at effective therapeutic concentrations and has strong application prospects in antibacterial photodynamic therapy.

[0040] In some examples, in the structure shown by general formula (I), R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, substituted or unsubstituted amino, substituted or unsubstituted amide, substituted or unsubstituted acyloxy, and p is 0 or 1; further, R1 is independently selected from hydrogen and dimethylamino.

[0041] In some of these examples, R2, R3, and R4 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C1-C3 alkoxy; further, R2, R3, and R4 are each independently selected from hydrogen, halogen, and methyl.

[0042] In some of these examples, L is selected from cyclohexylamine, aniline, benzylamine, oxygen- or nitrogen-containing five-membered heterocyclic amines, oxygen- or nitrogen-containing six-membered heterocyclic amines, or C3-C8 imine groups; further, L is selected from one of the following groups: , or .

[0043] In some of these examples, the naphthalimide compounds have any of the structures shown below: , , , , , , , , , , .

[0044] This invention also provides a method for preparing the above-mentioned thionaphthalene imide organic antibacterial photosensitizer or its pharmaceutically acceptable salt, comprising the following steps: (a) Compound B1 was reacted with compound NH2-L via an aminolysis reaction to prepare intermediate compound B2; (b) The intermediate compound B2 is subjected to a condensation reaction to prepare intermediate compound B3; (c) The intermediate compound B3 is prepared by a carbonyl thioreaction; The structural formulas of compound B1, intermediate compound B2, and intermediate compound B3 are shown below: The structural formula of compound B1 includes ; The structural formula of the intermediate compound B2 includes: ; The structural formula of the intermediate compound B3 includes .

[0045] In some specific examples, the reaction solvent for the aminolysis reaction includes N , N - One or more of dimethylformamide or toluene.

[0046] In some specific examples, the intermediate compound B2 undergoes a condensation reaction with a carboxylic acid compound or a carboxylic acid derivative compound; The carboxylic acid compound or acyl chloride compound includes one of the following structural formulas: or .

[0047] In some specific examples, the condensing agent in the condensation reaction includes 4-dimethylpyridine.

[0048] As an example of preparing compound K, when the carboxylic acid compound is The time-synthesis route 1 is shown below: (Synthesis Route 1) As a more specific example, the synthetic route 1-1 for preparing compound K1 is shown below:

[0049] As another example of the preparation of compound K, when the acyl chloride compound is The time-synthesis route 2 is shown below: (Synthesis Route 2) As a more specific example, the synthetic route 2-1 for preparing compound K2 is shown below:

[0050] This invention also provides the use of the aforementioned thionaphthalene imide organic antibacterial photosensitizers or pharmaceutically acceptable salts thereof in the preparation of antibacterial photodynamic therapy drugs, and the use of the aforementioned thionaphthalene imide organic antibacterial photosensitizers or pharmaceutically acceptable salts thereof in the preparation of reagents for selectively killing bacteria in bacteria and normal mammalian cells. The bacteria include, but are not limited to, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (MRSA). The thionaphthalene imide organic antibacterial photosensitizers provided by this invention can target bacteria and effectively kill bacteria under light irradiation for photodynamic therapy of bacterial infections, while exhibiting good biocompatibility.

[0051] The embodiments of the present invention will be described in detail below with reference to examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following examples that do not specify specific conditions should preferably refer to the guidelines given in this invention, or may be performed according to experimental manuals or conventional conditions in the art, or according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art. Reagents or instruments used that do not specify the manufacturer are all commercially available conventional products.

[0052] Example 1 Preparation of compound K1 Step (a): Weigh 1,8-naphthalenedicarboxylic anhydride (1-a) (1.0 g, 5.05 mmol) into a 100 mL round-bottom flask, add trans-1,4-diaminocyclohexane (1.15 g, 10.09 mmol), and 15 mL of [unclear - possibly a flask name]... N, N -Dimethylformamide was reacted at 150°C for 1 hour. After the reaction was complete, the insoluble matter was removed by filtration. N, N The filter cake was washed with dimethylformamide, and a large amount of deionized water was added to the filtrate. The mixture was stirred at room temperature for 20 minutes, resulting in the precipitation of a solid. The solid was filtered and dried to give 1.22 g of the intermediate compound 2-a, a white solid, with a yield of 82%. The structural formula of 2-a is shown below. Test data: 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 5.06-5.00 (m,1H), 2.89-2.84 (m, 1H), 2.71-2.61 (m, 2H), 2.01 (d, J = 12.4 Hz, 2H), 1.73 (d, J= 11.2 Hz, 2H), 1.40-1.30 (m, 2H). Step (b): Weigh 50 mg (0.17 mmol) of intermediate compound 2-a into a 25 mL round-bottom flask, add 5 mL of N,N-dimethylformamide, EDCI (40.7 mg, 0.21 mmol), HBTU (64.42 mg, 0.17 mmol), DIEA (73 μL, 0.42 mmol), and p-toluic acid (27.75 mg, 0.20 mmol), and stir at room temperature for 1 h. After the reaction is complete, remove the solvent under reduced pressure, add a small amount of dichloromethane to slurry, filter to obtain a filter cake, and purify the crude product by silica gel column chromatography (dichloromethane / methanol = 60:1, v / v) to obtain 55.0 mg of intermediate compound 3-a, a white solid, with a yield of 79%. The structural formula of 3-a is shown below. Test data: 1 H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 7.2 Hz, 2H), 8.20 (d, J = 7.6 Hz, 2H), 7.75 (t, J = 7.6 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 5.92 (d, J = 7.6 Hz, 1H), 5.12-5.06 (m, 1H), 4.19-4.15 (m, 1H), 2.88-2.79 (m,2H), 2.40 (s, 3H), 2.28 (d, J = 11.6 Hz, 2H), 1.82 (d, J = 11.2 Hz, 2H), 1.52-1.42 (m, 2H). Step (c): Weigh 50.0 mg (0.12 mmol) of intermediate compound 3-a into a 25 mL round-bottom flask, add 5 mL of toluene and Lawson's reagent (196.1 mg, 0.48 mmol), and react at 110 °C for 12 h under argon protection. After the reaction is complete, remove the solvent under reduced pressure, extract with dichloromethane, wash with deionized water, dry with anhydrous NaSO4, filter, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (dichloromethane / petroleum ether = 1:1, v / v) to give 20 mg of compound K1, a yellow solid, with a yield of 37%. The structural formula of K1 is shown below. Test data: 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 7.2Hz, 1H), 8.55 (d, J = 7.2 Hz, 1H), 8.16 (t, J = 7.6 Hz, 1H), 7.73–7.64 (m, 4H), 7.37 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.15 (t, J = 12.0 Hz, 1H),4.77-4.73 (m, 1H), 2.94–2.85 (m, 2H), 2.46 (d, J = 11.6 Hz, 2H), 2.37 (s, 3H), 1.96 (d, J = 11.2 Hz, 2H), 1.58-1.49 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 198.14,197.09, 161.71, 141.61, 139.70, 137.72, 133.80, 133.56, 131.91, 131.57,129.23, 128.49, 127.27 (d, J = 9.0 Hz), 126.74, 126.43, 123.79, 61.08, 54.29,31.66, 26.85, 21.44. HRMS (ESI) (m / z): [M+H] + calcd for C 26 H 24 N2OS2, 445.1403; found, 445.1411. (1-a), (2-a), (p-methylbenzoic acid), (3-a), (K1).

[0053] Example 2: Preparation of compound K2 Step (a) is the same as in Example 1; Step (b): Weigh 300.0 mg (1.02 mmol) of intermediate compound 2-a into a 25 mL round-bottom flask, add 10 mL of dichloromethane, DMAP (124.5 mg, 1.02 mmol), and 4-chlorobenzoyl chloride (196.2 mg, 1.12 mmol), and stir at room temperature for 1 h. After the reaction is complete, remove the solvent by rotary evaporation, dissolve in a small amount of ethyl acetate, adjust the pH to 9.0 by adding sodium hydroxide dropwise, and then adjust the pH to 7.0 by adding dilute hydrochloric acid dropwise. Filter and dry to obtain 325 mg of intermediate compound 3-b, a white solid, with a yield of 74%. The structural formula of compound 3-b is shown below. Test data: 1 H NMR (400 MHz, CDCl3) δ8.58 (d, J = 7.2 Hz, 2H), 8.20 (d, J = 8.0 Hz, 2H), 7.74 (q, J = 8.0 Hz, 4H), 7.41(d, J = 8.4 Hz, 2H), 5.94 (d, J = 7.6 Hz, 1H), 5.12-5.06 (m, 1H), 4.18 - 4.14 (m,1H), 2.88 - 2.79 (m, 2H), 2.27 (d, J = 12.0 Hz, 2H), 1.82 (d, J = 12.4 Hz, 2H),1.52–1.42 (m, 2H). Step (c) is essentially the same as in Example 1, except that intermediate compound 3-b is used. The prepared compound K2 is a yellow solid with a yield of 39%. The structural formula of compound K2 is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ9.02 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 6.4 Hz, 1H), 8.17 (t, J = 7.6 Hz, 2H), 7.74- 7.66 (m, 4H), 7.36 (d, J = 8.4 Hz, 2H), 6.19 - 6.13 (m, 1H), 4.74 - 4.70 (m,1H), 2.95 - 2.86 (m, 2H), 2.46 (d, J = 12.0 Hz, 2H), 1.97 (d,J = 10.8 Hz, 2H),1.53 - 1.49 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 197.15, 196.95, 161.77, 140.83,137.77, 137.35, 133.85, 133.60, 131.96, 131.64, 128.81, 128.56, 128.11,127.36, 127.27, 126.50, 123.85, 61.02, 54.55, 31.65, 26.86. HRMS (ESI) (m / z):[M+H] + calcd for C 25 H 21 ClN2OS2, 465.0857; found, 465.0862. (4-Chlorobenzoyl chloride), (3-b), (K2).

[0054] Example 3: Preparation of compound K3 Step (a) is the same as in Example 1; Step (b) is essentially the same as in Example 1, except that a carboxylic acid compound is used. The structural formula of carboxylic acid compound 2 in Example 3 is shown below. The prepared intermediate compound 3-c is a white solid with a yield of 84%. The structural formula of compound 3-c is shown below. Test data: 1 H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 7.2 Hz, 2H), 8.20 (d, J =8.0 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.75 (t, J = 8.0 Hz, 2H), 7.51 (d, J = 8.4Hz, 2H), 5.91 (d, J = 7.6 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.19 - 4.12 (m, 1H), 2.88 - 2.78 (m, 2H), 2.27 (d, J = 11.6 Hz, 2H), 1.82 (d, J = 11.6 Hz, 2H), 1.52 -1.42 (m, 2H). Step (c) is essentially the same as in Example 1, except that intermediate compound 3-c is used. The prepared compound K3 is a yellow solid with a yield of 37%. The structural formula of compound K3 is shown below, along with test data: 1 H NMR (400 MHz, DMSO- d 6)δ 10.15 (d, J = 7.6 Hz, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.50 (d, J = 7.2 Hz, 1H), 8.45 (d, J = 8.0 Hz, 2H), 7.88 - 7.80 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 6.08 -6.02 (m, 1H), 4.54 - 4.50 (m, 1H), 2.70 - 2.61 (m, 2H), 2.17 (d, J = 10.8 Hz, 2H), 1.90 (d, J = 10.8 Hz, 2H), 1.65 - 1.56 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) δ196.24, 195.12, 160.00, 140.80, 137.21, 136.65, 134.30, 134.23, 131.61,130.10, 129.20, 127.46, 125.43, 122.77, 97.62, 60.50, 54.42, 30.05, 26.45.HRMS (ESI) (m / z): [M+H] + calcd for C 25 H 21 IN2OS2, 557.0213; found, 557.0219. (Carboxylic acid compound 2), (3-c), (K3) Example 4: Preparation of compounds K4 and K5 Step (a) is basically the same as in Example 1, except for the different naphthalene anhydride compounds. The structural formula of naphthalene anhydride compound 1-b in Example 4 is shown below. The prepared intermediate compound 2-b is a yellow solid with a yield of 86%, and its structural formula is as follows; Step (b) is basically the same as in Example 3, except that intermediate compound 2-b is used. The prepared compound 3-d is a yellow solid with a yield of 85%. The structural formula of compound 3-d is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 7.2 Hz, 1H), 8.44 (t, J = 8.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 5.92 (d, J = 8.0 Hz, 1H), 5.11 - 5.05 (m, 1H), 4.16 - 4.13 (m, 1H), 3.10 (s,6H), 2.88 - 2.78 (m, 2H), 2.25 (d, J = 11.6 Hz, 2H), 1.80 (d, J = 11.2 Hz, 2H),1.51-1.41 (m, 2H). Step (c): Weigh 200.0 mg (0.60 mmol) of intermediate compound 3-d into a 25 mL round-bottom flask, add 15 mL of toluene and Lawson's reagent (570.2 mg, 2.39 mmol), and react at 110 °C for 12 h under argon protection. After the reaction is complete, remove the solvent under reduced pressure, extract with dichloromethane, wash with deionized water, dry with anhydrous NaSO4, filter, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (dichloromethane / petroleum ether = 1:1, v / v). After rotary evaporation and concentration, it is separated and purified by C18 column chromatography (mobile phase: acetonitrile 100%) to obtain 35 mg of compound K4, a red solid, with a yield of 17%; and 47 mg of compound K5, a red solid, with a yield of 22%.

[0055] The structural formula of compound K4 is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ 8.97 (d, J =8.8 Hz, 1H), 8.54 (d, J = 7.2 Hz, 1H), 8.38 (d, J= 8.4 Hz, 1H), 7.73 (d, J = 8.4Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.29 - 6.23 (m, 1H), 4.72 - 4.69 (m, 1H), 3.16 (s, 6H), 2.94 - 2.85 (m, 2H), 2.44 (d, J = 11.2 Hz, 2H), 1.94 (d, J = 11.2 Hz,2H), 1.53 - 1.50 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 197.08, 195.19, 170.82,162.29, 157.09, 141.88, 140.13, 137.75, 131.94, 131.42, 128.33, 125.10,124.32, 123.92, 121.67, 113.76, 97.71, 54.61, 44.74, 31.62, 29.85, 26.74.HRMS (ESI) (m / z): [M+H] + calcd for C 27 H 26 IN3OS2, 600.0635; found, 600.0643. The structural formula of compound K5 is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ 9.04 (d, J =7.6 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.09 (d,J = 8.4 Hz, 1H), 6.21 - 6.15 (m, 1H), 4.71 - 4.69 (m, 1H), 3.12(s, 6H), 2.91 (d, J = 11.6 Hz, 2H), 2.44 (d, J = 11.2 Hz, 2H), 1.95 (d, J = 11.6Hz, 2H), 1.55 - 1.49 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 197.09, 196.91,169.40, 161.81, 157.12, 141.87, 137.88, 137.74, 133.52, 131.12, 128.95,128.62, 128.33, 125.19, 125.00, 113.72, 97.70, 61.01, 54.60, 44.90, 31.65,26.87. HRMS (ESI) (m / z): [M+H] + calcd for C 27 H 26 IN3OS2, 600.0635; found, 600.0641. (1-b), (2-b), (3-d), (K4), (K5).

[0056] Example 5 Preparation of compounds K6 and K7 Step (a) is the same as in Example 4; Step (b) is basically the same as in Example 4, except that a different carboxylic acid compound 3 is used. The prepared compound 3-e is a yellow solid with a yield of 77%. The structural formula of compound 3-e is shown below, along with test data: 1 H NMR (400 MHz, CDCl3)δ 8.54 (d, J = 6.4 Hz, 1H), 8.44 (dd, J = 8.0, 4.4 Hz, 2H), 7.87 (d, J = 2.0 Hz,1H), 7.68 - 7.64 (m, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d,J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 5.11 - 5.05 (m, 1H), 4.18 - 4.10 (m, 1H), 3.11 (s, 6H), 2.85 - 2.79 (m, 2H), 2.25 (d, J = 11.2 Hz, 2H), 1.81 (d, J = 11.6 Hz, 2H), 1.53-1.44 (m, 2H). Step (c) is essentially the same as in Example 4, except that intermediate compound 3-e is used. Compound K6 was prepared as a red solid with a yield of 21%; compound K7 was prepared as a red solid with a yield of 27%.

[0057] The structural formula of compound K6 is shown below, along with test data: 1 H NMR (400 MHz, DMSO- d 6) δ 10.29 (d, J = 8.0 Hz, 1H), 8.82 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 7.2Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.75 - 7.69 (m, 3H), 7.14 (d, J = 8.8 Hz, 1H), 6.21 - 6.15 (m, 1H), 4.50 - 4.46 (m, 1H), 3.21 (s, 6H), 2.66 (d, J = 10.0 Hz, 2H), 2.16 (d, J = 10.8 Hz, 2H), 1.82 (d, J = 10.8 Hz, 2H), 1.64 - 1.56 (m, 2H). 13CNMR (100 MHz, CDCl3) δ 195.29, 195.15, 162.31, 157.11, 142.04, 140.15,135.29, 132.93, 131.94, 131.45, 130.51, 128.80, 125.90, 125.09, 124.30,123.89, 121.63, 113.75, 60.32, 54.78, 44.74, 31.57, 26.73. HRMS (ESI) (m / z):[M+H] + calcd for C 27 H 25 Cl2N3OS2, 542.0889; found, 542.0896. The structural formula of compound K7 is shown below, along with test data: 1 H NMR (400 MHz, DMSO- d 6)δ 10.29 (d, J =7.6 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.34 - 8.31 (m,1H), 7.93 (d, J = 2.0 Hz, 1H), 7.73 - 7.67 (m, 3H), 7.20 (d, J = 8.8 Hz, 1H), 6.12 - 6.07 (m, 1H), 4.50-4.47 (br, 1H), 3.14 (s, 6H), 2.68 (d, J = 11.0 Hz, 2H), 2.17 (d, J = 11.2 Hz, 2H), 1.86 (d, J = 10.8 Hz, 2H), 1.64–1.56 (m, 2H). 13CNMR (100 MHz, CDCl3) δ 196.89, 195.30, 161.84, 157.14, 142.04, 137.88,135.28, 133.52, 132.91, 131.14, 130.49, 128.93, 128.78, 128.62, 125.91,125.18, 124.98, 115.83, 113.70, 60.95, 54.78, 44.90, 31.60, 26.86. HRMS (ESI)(m / z): [M+H] + calcd for C 27 H 25 Cl2N3OS2, 542.0889; found, 542.0893. (Carboxylic acid compound 3), (3-e), (K6), (K7).

[0058] Example 6: Preparation of compounds K8 and K9 Step (a) is the same as in Example 4; Step (b) is basically the same as in Example 4, except that a different carboxylic acid compound 4 is used. The prepared compound 3-f is a yellow solid with a yield of 75%. The structural formula of compound 3-f is shown below, along with test data: 1 H NMR (400 MHz, DMSO- d 6) δ 8.49 (d, J = 8.0 Hz, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.97 (dd, J = 8.0, 6.4 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.70 (dd, J = 8.8, 1.6 Hz, 1H), 7.51 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.96 - 4.90 (m,1H), 3.88 - 3.84 (m, 1H), 3.08 (s, 6H), 2.66 - 2.56 (m, 2H), 1.98 (d, J= 11.2Hz, 2H), 1.71 (d, J = 10.8 Hz, 2H), 1.56 - 1.47 (m, 2H). Step (c) is essentially the same as in Example 4, except that intermediate compound 3-f is used. Compound K8 was prepared as a red solid with a yield of 19%; compound K9 was prepared as a red solid with a yield of 23%.

[0059] The structural formula of compound K8 is shown below, along with test data: 1 H NMR (400 MHz, DMSO- d 6) δ 10.23 (d, J = 8.0 Hz, 1H), 8.82 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 7.2Hz, 1H), 7.93 - 7.90 (m, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.20 - 6.14 (m, 1H), 4.49 -4.47 (m, 1H), 3.21 (s, 6H), 2.66 (d, J = 10.8 Hz, 2H), 2.15 (d, J = 11.2 Hz, 2H), 1.82 (d, J = 10.8 Hz, 2H), 1.64 - 1.55 (m, 2H). 13 C NMR (100 MHz, DMSO- d6) δ193.37, 192.88, 161.54, 159.34, 156.87, 139.90, 138.78, 132.37, 131.69,128.21, 125.13, 124.88, 123.05, 122.05, 118.99, 114.33, 114.07, 113.01,84.93, 59.60, 54.66, 44.27, 30.04,26.36. HRMS (ESI) (m / z): [M+H] + calcd forC 27 H 25 FIN3OS2, 618.0541; found, 618.0539. The structural formula of compound K9 is shown below, along with test data: 1 H NMR (400 MHz, DMSO- d 6) δ 10.23 (d, J = 7.6 Hz, 1H), 8.92 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.10 -6.05 (m, 1H), 4.49- 4.47 (m, 1H), 3.13 (s, 6H), 2.67 (d, J = 10.0 Hz, 2H), 2.15 (d, J = 11.2 Hz, 2H), 1.85 (d, J = 10.8 Hz, 2H), 1.63 - 1.55 (m, 2H). 13 C NMR (100 MHz, DMSO- d6) δ195.52, 193.43, 161.77, 160.85, 159.36, 156.84, 141.95, 138.82, 137.45,133.45, 132.02, 127.97, 127.70, 125.15, 124.97, 123.48, 114.34, 114.08,113.31, 113.14, 84.95, 79.16, 60.47, 54.66, 44.38, 30.08, 26.54. HRMS (ESI)(m / z): [M+H] + calcd for C 27 H 25 FIN3OS2, 618.0541; found, 618.0539. (Carboxylic acid compound 4), (3-f), (K8), (K9).

[0060] Example 7 Preparation of compounds K10 and K11 Step (a): Weigh 50.0 mg (0.2 mmol) of compound 1-b into a 25 mL round-bottom flask, dissolve it in 4 mL of anhydrous ethanol, add N-aminoethylpiperazine (420 μL, 0.41 mmol), and then stir the reaction at 80 °C for 2 hours. After the reaction is complete, remove the solvent by rotary evaporation to obtain the crude product. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 10:1, v / v), and dried under vacuum to give 35 mg of compound 2-c as a yellow solid, with a yield of 48%. The structural formula of compound 2-c is shown below. Test data: 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 7.2 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.4, 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.08 (s, 6H), 2.87 (t, J =4.4 Hz, 4H), 2.66 (t, J= 7.2Hz, 2H), 2.57 (s, 4H), 2.19 (s, 1H). Step (b) is basically the same as in Example 6, except that intermediate compound 2-c is used. The prepared compound 3-g is a yellow solid with a yield of 43%. The structural formula of compound 3-g is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 7.2 Hz, 1H), 8.46 - 8.42 (m, 2H), 7.77 (dd, J = 8.0, 6.4Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.12 - 7.08 (m, 2H), 6.92 (dd, J = 8.0, 1.6Hz, 1H), 4.32 (t, J = 6.8 Hz, 2H), 3.72 (s, 2H), 3.37 (s, 2H), 3.10 (s, 6H), 2.74 (t, J = 6.8 Hz, 2H), 2.66 - 2.56 (m, 4H). Step (c) is essentially the same as in Example 6, except that intermediate compound 3-g is used. Compound K10 was prepared as a red solid with a yield of 25%; compound K11 was prepared as a red solid with a yield of 28%.

[0061] The structural formula of compound K10 is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ 8.97 (d, J =8.8 Hz, 1H), 8.56 (d, J = 6.8 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.0, 6.4 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 6.81 (dd, J = 8.0, 2.0 Hz, 1H), 4.94 (t, J= 7.2 Hz, 2H), 4.37 (br,2H), 3.57 (t, J = 4.8 Hz, 2H), 3.17 (s, 6H), 2.87 (t, J = 7.2 Hz, 2H), 2.83 (t, J =4.8 Hz, 2H), 2.65 (t, J = 4.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 197.20, 193.43,162.79, 162.25, 160.32, 157.40, 144.95 (d, J = 6.6 Hz), 139.65, 139.25, 132.31,131.86, 128.96, 125.03, 124.06, 123.28-123.14 (m), 121.12, 113.78, 113.50,81.54 (d, J = 25.3 Hz), 64.11, 53.51, 52.88, 52.32, 49.47, 44.77, 43.91. HRMS(ESI) (m / z): [M+H] + calcd for C 27 H 26 FIN4OS2, 633.0650; found, 633.0659. The structural formula of compound K11 is shown below, along with test data: 1 H NMR (400 MHz, CDCl3) δ 9.05 (d, J =7.6 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.0, 6.4 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H), 6.81 (dd, J = 8.0, 2.0 Hz, 1H), 4.93 (t, J= 7.2 Hz, 2H), 4.37 (t, J =4.8 Hz, 2H), 3.57 (t, J = 4.8 Hz, 2H), 3.14 (s, 6H), 2.87 (t, J = 7.2 Hz, 2H), 2.83 (t, J = 4.8 Hz, 2H), 2.65 (t, J = 4.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ197.24, 195.11, 162.80, 161.67, 160.34, 157.51, 144.95 (d, J = 6.7 Hz), 139.68,137.13, 133.97, 131.52, 128.92, 128.39, 125.17, 125.02, 123.17 (d, J = 3.5 Hz),114.66, 113.77 - 113.51 (m), 81.56 (d, J = 25.6 Hz), 53.90, 53.50, 52.87,52.31, 49.45, 44.91, 44.17. HRMS (ESI) (m / z): [M+H] + calcd for C 27 H 26 FIN4OS2,633.0650; found, 633.0660. (N-aminoethylpiperazine), (2-c), (3-g), (K10), (K11).

[0062] Test Example 1 The synthesized compounds were tested for antibacterial activity in accordance with the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Test strains included methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300) and vancomycin-resistant Staphylococcus aureus (VISA, XN108).

[0063] The experimental procedure is as follows: Adjust the concentration of the bacterial suspension to 1 × 10⁻⁶. 6 CFU / mL; the test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution. The stock solution was serially diluted with culture medium using a two-fold dilution method, and an equal volume of bacterial suspension was added to each well. The 96-well plate was divided into two treatment groups: the "Light" group was irradiated with a 510 nm wavelength light source for 30 minutes after bacterial addition; the "Dark" group was kept in the dark throughout the treatment. After treatment, all wells were incubated at 37°C for 16–20 hours. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of compound that completely inhibited bacterial growth as observed visually, and was verified by measuring the absorbance at 600 nm using a microplate reader (Dark: no light; Light: light). The test results are shown in Table 1.

[0064] Table 1. Minimum inhibitory concentration (MIC) values ​​of the compounds

[0065] As shown in Table 1, under light conditions, the thionaphthalene imide-based organic antibacterial photosensitizers provided in this invention exhibit excellent inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VISA), with their minimum inhibitory concentrations (MICs) significantly superior to those under dark conditions and those against the positive control drug vancomycin. This fully demonstrates the highly efficient photodynamic antibacterial properties of this class of compounds and confirms their promising application prospects in the development of novel photodynamic antibacterial drugs.

[0066] Test Example 2 Taking the thionaphthalene imide photosensitizer K9 synthesized in this invention as an example, the photophysical properties of K9 and its oxygen carbonyl precursor (unsulfurized) were characterized. Figure 1 As shown, compared with the oxygen carbonyl precursor, K9 exhibits a redshift of approximately 70-80 nm in its UV-Vis maximum absorption peak, accompanied by significant fluorescence quenching. These spectral characteristics are consistent with the effect of sulfur atom introduction promoting intersystem crossing, confirming the typical structural features of K9 as a thiophotosensitive agent.

[0067] Test Example 3 Characterization of the in vitro ROS generation capacity of the thionaphthalene imide organic photosensitizer K9.

[0068] The quantum yield of singlet oxygen (¹O₂) was determined using the DPBF probe method. Figure 2 As shown, the ¹O2 quantum yield of K9 is about three times that of the commercially available standard Rose Bengal (RB), indicating that it has excellent type II photodynamic activity.

[0069] To investigate its photodynamic properties under hypoxic conditions, we examined the reactive oxygen species generated during the type I photodynamic process of compound K9. For example... Figure 3 As shown in figure a, the hydroxyl radical (•OH) signal of K9 was qualitatively detected using electron paramagnetic resonance (EPR) technology; and the presence of superoxide anion radical (O2) in compound K9 was confirmed using the DHR123 fluorescent probe method. •- The ability to generate () Figure 3 b). The above results demonstrate that K9 possesses the ability to generate type I reactive oxygen species.

[0070] In addition, under bacterial conditions, the overall ROS generation capacity of K9 was detected using the clinically commonly used reactive oxygen species indicator DCFH-DA. Under green light irradiation, the fluorescence emission intensity of the K9 / DCFH-DA mixture at 525 nm was significantly higher than that of the unilluminated group and the control group. Figure 4 This fully demonstrates that K9 can effectively generate reactive oxygen species inside bacteria.

[0071] In summary, the thionaphthalene imide photosensitizer K9 exhibits both efficient generation of type I and type II reactive oxygen species, demonstrating excellent ROS generation performance.

[0072] Test Example 4 To optimize the antibacterial application conditions of photosensitizer K9, we systematically investigated the effects of three key factors—photosensitizer concentration, pre-incubation time, and light exposure time—on its bactericidal efficacy.

[0073] MRSA bacterial suspensions were co-incubated with different final concentrations of K9 for 30 min, then exposed to green light for 30 min, followed by plate counting. Results are as follows: Figure 5 As shown, the sterilization rate increased significantly with increasing K9 concentration; at a concentration of 0.025 μg / mL, the sterilization rate reached over 80%. Subsequent experiments selected 0.025 μg / mL as the baseline concentration for optimizing other parameters.

[0074] At a K9 concentration of 0.025 μg / mL, the bacterial culture was pre-incubated with a photosensitizer for different times (0, 5, 10, 30, 60 min), followed by a fixed duration of light exposure (30 min). The results are as follows: Figure 6 As shown, the bactericidal rate significantly increased with prolonged pre-incubation time. Within 30 minutes, K9 could essentially complete its entry into cells or bind to bacterial targets, thus exhibiting good antibacterial activity.

[0075] Under the selected K9 concentration of 0.025 μg / mL and a pre-incubation period of 30 minutes, the samples were exposed to light for different durations (0, 5, 10, 30, 60 min). The results are as follows: Figure 7As shown, the sterilization rate increases with the extension of light exposure time, reaching its maximum value in 30 minutes.

[0076] The above results indicate that the antibacterial efficacy of K9 is positively correlated with photosensitizer concentration and light exposure time within the investigated range. Considering both bactericidal efficiency and ease of clinical application, the preferred antibacterial conditions are: K9 pre-incubated with bacterial solution for 30 minutes, followed by green light irradiation for 30 minutes.

[0077] Test Example 5 To assess the blood compatibility of the photosensitizer K9, we performed an in vitro hemolysis experiment. Different concentrations of K9 were co-incubated with red blood cell suspensions for 1 hour, followed by centrifugation and observation of the supernatant. Figure 8 As shown in Figure a, the supernatant of all tested concentration groups was colorless and transparent, and a dense red blood cell precipitate formed at the bottom of the test tubes, indicating that hemolysis did not occur. The absorbance of the supernatant at 540 nm was quantitatively measured using an ELISA reader, and the hemolysis rate was calculated. The results are as follows: Figure 8 As shown in b, even at concentrations as high as 64 μg / mL, the hemolysis rate of K9 remained below the 5% biosafety threshold. This result indicates that K9 poses no risk of hemolysis within the tested concentration range and exhibits good blood compatibility.

[0078] Test Example 6 The toxicity of photosensitizer K9 to mammalian L929 cells was evaluated using the CCK-8 assay. L929 cells were cultured at 1 × 10⁶ cells per well. 4 Cells were seeded at a density of [number] cells / well in 96-well plates. After cell attachment, the medium was replaced with fresh medium containing different concentrations of K9. The plates were divided into light and dark groups: the light group was exposed to green light for 30 minutes, while the dark group was kept in the dark throughout the process. After co-incubation for 24 hours, the culture medium was discarded, and CCK-8 solution was added and reacted for 30 minutes. The absorbance at 450 nm was then measured using a microplate reader. Cell viability was calculated by comparing the absorbance values ​​of the experimental group and the control group. Figure 9 As shown, at concentrations as high as 64 μg / mL, the survival rate of L929 cells in both the light and dark groups was higher than 85%. This result indicates that within the specified concentration range, K9 exhibits no significant phototoxicity or dark toxicity to normal mammalian cells, demonstrating excellent biocompatibility.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A thionaphthalene imide-based organic antibacterial photosensitizer or a pharmaceutically acceptable salt thereof, characterized in that, It has the structure shown in the general formula (I): General Formula (I) R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1 groups. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy, substituted or unsubstituted C1 C3 alkylthio group, substituted or unsubstituted amino group, substituted or unsubstituted amide group, substituted or unsubstituted acyloxy group; p represents the number of R1 substituents on the benzene ring, and p is any integer from 0 to 6; R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted amino groups, and substituted or unsubstituted C1 groups, respectively. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy group; X, Y, and Z are each independently selected from oxygen or sulfur; L is selected from substituted or unsubstituted aniline, substituted or unsubstituted benzylamine, five-membered heterocyclic amine, six-membered heterocyclic amine, C3-C8 alkylamine, and C3-C8 cycloalkylamine. Indicates the connection site.

2. The thionaphthalene imide organic antibacterial photosensitizer or its pharmaceutically acceptable salt as described in claim 1, characterized in that, R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1 groups. C3 alkyl, substituted or unsubstituted C1 C3 alkoxy, substituted or unsubstituted C1 C3 alkylthio group, substituted or unsubstituted amino group, substituted or unsubstituted amide group, substituted or unsubstituted acyloxy group; p is 0 or 1; R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, and C1 groups, respectively. C3 alkyl-substituted or unsubstituted amino groups, substituted or unsubstituted C1 C3 alkyl, substituted or unsubstituted C1 C3 alkoxy group; L is selected from cyclohexylamine, aniline, benzylamine, oxygen- or nitrogen-containing five-membered heterocyclic amines, oxygen- or nitrogen-containing six-membered heterocyclic amines, or C3-C8 imideamine groups.

3. The thionaphthalene imide organic antibacterial photosensitizer or its pharmaceutically acceptable salt as described in claim 2, characterized in that, R1 is independently selected from hydrogen or dimethylamino; R2, R3, and R4 are independently selected from hydrogen, halogen, and methyl, respectively; X, Y, and Z are each independently selected from oxygen or sulfur; L is selected from one of the following groups: , or .

4. The thionaphthalene imide organic antibacterial photosensitizer or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, characterized in that, It has any of the following structures: 。 5. A method for preparing the thionaphthalene imide organic antibacterial photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, comprising the following steps: (a) Compound B1 was reacted with compound NH2-L via an aminolysis reaction to prepare intermediate compound B2; (b) The intermediate compound B2 is subjected to a condensation reaction to prepare intermediate compound B3; (c) The intermediate compound B3 is subjected to a carbonyl thioreaction to prepare the compound; The structural formulas of compound B1, intermediate compound B2, and intermediate compound B3 are shown below: The structural formula of compound B1 includes ; The structural formula of the intermediate compound B2 includes: ; The structural formula of the intermediate compound B3 includes .

6. The preparation method according to claim 5, characterized in that, The intermediate compound B2 undergoes a condensation reaction with carboxylic acid compounds or acyl chloride compounds; The structural formula of the carboxylic acid compound or acyl chloride compound is as follows: or .

7. A photosensitizer, characterized in that, This includes the thionaphthalene imide organic antibacterial photosensitizer or its pharmaceutically acceptable salt as described in any one of claims 1 to 4, or the thionaphthalene imide organic antibacterial photosensitizer or its pharmaceutically acceptable salt prepared by the preparation method according to any one of claims 5 to 6.

8. The use of the thionaphthalene imide organic antibacterial photosensitizers as described in claims 1 to 4, or pharmaceutically acceptable salts thereof, in the preparation of antibacterial photodynamic therapy drugs.

9. The use of the thionaphthalene imide organic antibacterial photosensitizers as described in claims 1 to 4, or pharmaceutically acceptable salts thereof, in the preparation of reagents for selectively killing bacteria in both bacteria and normal mammalian cells.

10. The application according to claim 9, characterized in that: The bacteria include one or more of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, Enterococcus faecalis, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter baumannii, and the normal cells are mouse fibroblast L929 cells and mouse erythrocytes.

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