Triterpene derivative or pharmaceutically acceptable salt or solvate thereof, and antibacterial use thereof

Abstract

The present application relates to a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, and antibacterial use thereof. In the compound represented by formula (I), formula (a) is -CH=CH- or -CH2-CHR1-, R1 is a substituted or unsubstituted pyranocyclic glycosyl or a substituted or unsubstituted furanocyclic glycosyl, R8 is a substituent having 5-20 carbon atoms, R2 and R3 are each a monovalent group or are connected to one another to form a six-membered carbocyclic ring with adjacent carbon atoms, and the six-membered carbocyclic ring may be substituted or unsubstituted.

Description

Triterpene derivatives or pharmaceutically acceptable salts or solvates thereof and antibacterial uses thereof

[0001] Related applications

[0002] This application claims priority to Chinese patent application No. 202311237384.4, filed on September 22, 2023, entitled “Application of triterpenoid compounds or pharmaceutically acceptable salts thereof in the preparation of antibacterial compositions,” the entire text of which is hereby incorporated by reference. Technical Field

[0003] The present application relates to the field of antibacterial technology, and in particular to triterpene derivatives or pharmaceutically acceptable salts or solvates thereof and their antibacterial uses. Background Art

[0004] With the widespread use of antibiotics, especially their overuse, bacterial resistance to commonly used antibiotics has continued to increase, and the continuous emergence of drug-resistant bacteria has reduced the effectiveness of antibiotics. This has led to new challenges in the treatment of bacterial infections, and some drug-resistant bacterial infections even have no effective treatment options. For example, for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), current antibiotics are less than ideal in their effectiveness.

[0005] Summary of the Invention

[0006] In the first aspect of the present application, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof,

[0007] in, is -CH=CH- or -CH2-CHR1-;

[0008] R1 is selected from any one of a pyranose ring glycoside, a pyranose ring glycoside with one -OH acetylated, a furanose ring glycoside, and a furanose ring glycoside with one -OH acetylated; and any of the foregoing groups in which one -OH group is acetylated;

[0009] R2 is -(CH2)2-C(=O)-O-R4 and R3 is -CH(=CH2)-CH3, or R2 and R3 are both -(CR5R6)2- and R2 and R3 form a saturated 6-membered ring with adjacent carbon atoms;

[0010] Any R5 and any R6 are independently H, methyl or -OR7;

[0011] R4 and any one R7 are independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocycloalkyl and substituted or unsubstituted phenyl C 1-6 Alkyl; wherein, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 are selected from O and N, C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is one or more;

[0012] Substituted C 1-6 Alkyl, substituted C 3-6 Cycloalkyl, substituted C 3-6 Heterocycloalkyl and substituted phenyl C 1-6 In the alkyl group, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and phenyl C 1-6 The H in the alkyl group is independently substituted by one or more Q1, and any Q1 is independently selected from -F, -Cl, -Br, -NH2, -NO2, acetyl, acetoxymethyl (CH3C(=O)-O-CH2-), C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted -[O-divalent C 5-6 heterocycloalkyl] n -OH;

[0013] Substituted-[O-divalent C 5-6 heterocycloalkyl] n -OH, divalent C 5-6 The H in the heterocycloalkyl group is substituted by one or more Q2, any Q2 being independently -CH3 or -OH, -CH3 and -OH being in the divalent C 5-6 The number of all Q2 in the heterocycloalkyl group is independently 1 to 4, and the divalent C 5-6 The ring atoms in the heterocycloalkyl group include heteroatoms X2, wherein the heteroatoms X2 are selected from O and N, divalent C 5-6 The number of the heteroatom X2 in the heterocycloalkyl group is one or more, and n is 0, 1, 2, 3, 4 or 5;

[0014] R8 is selected from:

[0015] where R aand R b are independently selected from H, -OH, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-O-, substituted or unsubstituted C 3-6 Cycloalkyl-O- and substituted or unsubstituted C 3-6 Heterocycloalkyl-O-, wherein the substituted C 1-6 Alkyl, substituted C 1-6 Alkyl-O-, substituted C 3-6 Cycloalkyl-O- and substituted C 3-6 Heterocycloalkyl-O-, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O- and C 3-6 Heterocycloalkyl-O- is independently substituted by one or more Q3, any Q3 being independently selected from: -OH, methyl, ethyl, acetyl, methoxy, ethoxy, -F, -Cl and -Br; C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X3, wherein the heteroatoms X3 are selected from O and N; R c Any one independently selected from trifluoroacetyl, trichloroacetyl and tribromoacetyl.

[0016] In a second aspect of the present application, an antibacterial composition is provided, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0017] In the third aspect of the present application, there is provided use of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of an antibacterial composition.

[0018] In a fourth aspect of the present application, an antibacterial drug is provided, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0019] In the fifth aspect of the present application, a method for treating, improving or preventing bacterial infection is provided, comprising administering an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.

[0020] In the sixth aspect of the present application, a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided for use in treating, improving or preventing bacterial infection or a disease caused by bacterial infection.

[0021] In some embodiments, the disease caused by bacterial infection includes a disease caused by drug-resistant bacterial infection, and the disease caused by drug-resistant bacterial infection includes a disease caused by infection with at least one of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and linezolid-resistant Enterococcus.

[0022] In the seventh aspect of the present application, a product is provided, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0023] In the eighth aspect of the present application, a method for using a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof as an antibacterial active substance is provided, comprising adding the compound or a pharmaceutically acceptable salt or solvate thereof to a desired product or coating the surface of the product.

[0024] In some embodiments, the product includes at least one of medical devices, daily necessities, cosmetics and packaging supplies, and the daily necessities include one or more of cleaning supplies, sanitary care products, bedding, kitchen utensils, dining utensils and toys.

[0025] In a ninth aspect of the present application, a disinfectant is provided, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0026] In the tenth aspect of the present application, a disinfection method is provided, comprising applying a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof to a target object in need.

[0027] In the eleventh aspect of the present application, there is provided the use of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof as a disinfectant; said use is for non-therapeutic purposes.

[0028] In the twelfth aspect of the present application, a FtsZ protein inhibitor is provided, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0029] In the thirteenth aspect of the present application, a method for inhibiting FtsZ protein is provided, comprising contacting cells with an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0030] In the fourteenth aspect of the present application, there is provided use of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof as an FtsZ protein inhibitor.

[0031] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof has a killing effect on any one, any two or all of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci and linezolid-resistant Enterococci.

[0032] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof also has a killing effect on one, multiple or all of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

[0033] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof is used in any suitable form of any of the following groups:

[0034] Preparations shown in Group A: tablets, capsules, granules, pills, ointments, solutions, suspensions, emulsions and creams;

[0035] Preparations shown in Group B: oral solution, lozenge, injection, suppository, spray, drop, patch and tube feeding preparations;

[0036] The form shown in group C: surface coating of a solid product and dopant in a solid product, wherein the solid product at least includes a plastic product.

[0037] After a large number of experimental explorations, the applicant of the present application unexpectedly discovered that a class of triterpene derivatives has high bactericidal activity against some antibiotic-resistant strains. In addition, it also has broad-spectrum antibacterial activity and has a strong killing effect on a variety of common pathogenic bacteria. Specifically, the compound represented by formula (I) has high bactericidal activity against at least one of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and linezolid-resistant enterococci. In addition, it also has a strong killing effect on one, multiple or all of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, vancomycin-resistant enterococci, linezolid-resistant enterococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the conventional technology, the following briefly introduces the drawings required for use in the embodiments or the conventional technology descriptions. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0039] Figures 1A and 1B are schematic diagrams of the binding mode of triterpene derivatives and FtsZ in one embodiment of the present application: Figure 1A is a visual schematic diagram of the docking of compound C8 and FtsZ, and Figure 1B is a surface diagram of the interaction between compound C8 and FtsZ.

[0040] Figures 2A and 2B are schematic diagrams of the binding mode of triterpene derivatives and FtsZ in one embodiment of the present application: Figure 1A is a visual schematic diagram of the docking of compound C11 and FtsZ, and Figure 1B is a surface diagram of the interaction between compound C11 and FtsZ.

[0041] Figure 3 is a schematic diagram of the binding pocket of FtsZ, in which the light-colored part is the binding pocket region. DETAILED DESCRIPTION

[0042] In order to make the above-mentioned objects, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application are described in detail below with reference to the accompanying drawings. In the following description, many specific details are set forth to facilitate a full understanding of the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present application, so the present application is not limited by the specific embodiments disclosed below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the technical field of the present application. The terms used herein in the specification of the present application are only for the purpose of describing the embodiments and embodiments and are not intended to limit the present application.

[0043] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0044] As used herein, the terms "and / or," "or / and," and "and / or" include any one of two or more of the listed items, as well as any and all combinations of the listed items, including any combination of any two, any more, or all of the listed items. For example, "A and / or B" includes three parallel options: A, B, and the combination of A and B.

[0045] In this application, “multiple”, “many”, “multiple times”, “multiples”, “several”, etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, “one or more” means one or more than or equal to two.

[0046] In this application, unless otherwise specified, "one or more" refers to any one of the listed items or any combination of the listed items. Similarly, "one or more" and other similar expressions that refer to "one or more" are also understood in the same way unless otherwise specified.

[0047] As used herein, "combination thereof", "any combination thereof", "any combination thereof" and the like include all suitable combinations of any two or more of the listed items.

[0048] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc. shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0049] Herein, the terms "preferred," "better," "more preferred," and "suitable" are used solely to describe preferred implementations or examples and should not be construed as limiting the scope of protection of this application. If multiple "preferred" terms appear in a technical solution, each "preferred" term is considered independent unless otherwise specified and there are no contradictions or mutual constraints.

[0050] In this application, the terms "further," "further," "particularly," "for example," "such as," "example," and "for example" are used for descriptive purposes to indicate that the preceding and following technical solutions are related in terms of the content covered, but should not be construed as limiting the preceding technical solution or the scope of protection of this application. In this application, unless otherwise specified, A (such as B) means that B is a non-limiting example of A, and it is understood that A is not limited to B.

[0051] In this application, the terms "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If a technical solution contains multiple "optional" clauses, each "optional" clause is independent unless otherwise specified and there are no contradictions or constraints.

[0052] In this application, the terms "first," "second," "third," "fourth," etc. in "the first aspect," "the second aspect," "the third aspect," "the fourth aspect," etc. are used for descriptive purposes only and should not be understood as indicating or implying relative importance or quantity, nor should they be understood as implicitly indicating the importance or quantity of the indicated technical features. Furthermore, "first," "second," "third," "fourth," etc. serve only as non-exhaustive enumeration and description, and should be understood not to constitute a closed-ended limitation on quantity.

[0053] The terms "contain", "include" and "include" used in this application are synonymous, which are inclusive or open-ended and do not exclude additional, uncited members. Unless otherwise specified, open technical features or technical solutions described with words such as "contain", "include" and "include" can be regarded as providing both closed features or solutions consisting of the listed members and open features or solutions that include additional members in addition to the listed members. For example, A includes a1, a2 and a3. Unless otherwise specified, it may also include other members or may not include additional members. It can be regarded as providing both the feature or solution of "A consists of a1, a2 and a3" or "A is selected from a1, a2 and a3", and the feature or solution of "A includes not only a1, a2 and a3, but also other members". The "members" involved here can be materials or components, structures, elements, instruments, etc., and can also be actions, conditions for the occurrence of actions, timing, states, etc.

[0054] In this application, the technical features or technical solutions described in open language include closed technical features or technical solutions composed of the listed contents, and also include open technical features or technical solutions containing the listed contents.

[0055] In this application, when referring to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional numerical values ​​in the numerical interval is considered to be continuous and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical interval, and each numerical value between the two numerical endpoints. Unless otherwise specified, when a numerical interval only refers to an integer in the numerical interval, including the two endpoint integers of the numerical range and each integer between the two endpoints, is equivalent to directly enumerating each integer. When multiple numerical ranges are provided to describe a feature or characteristic, these numerical ranges can be merged. In other words, unless otherwise specified, the numerical range disclosed herein should be understood to include any and all subranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, a percentage, a ratio, etc. "Numerical interval" allows broadly including numerical interval types such as percentage intervals, ratio intervals, and ratio intervals.

[0056] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited in their entirety and for all purposes. When cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When cited documents are involved in this application, the examples and preferred embodiments of the cited relevant technical features may also be incorporated into this application as references, but are limited to the ability to implement this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be adaptively amended according to the description in this application.

[0057] In this application, if a method flow involves multiple steps, unless otherwise specified herein, there is no strict order restriction on the execution of these steps, and they can be executed in an order other than the order described. Moreover, any step can include multiple sub-steps or multiple stages, and these sub-steps or stages do not necessarily need to be completed at the same time, but can be executed at different times, and their execution order is not necessarily sequential, but can be executed in turn, alternating, or simultaneously with other steps or parts of sub-steps or stages of other steps.

[0058] The mass or weight of the relevant components mentioned in the examples of this application may not only refer to the specific content of each component, but also represent the proportional relationship of the mass or weight of each component. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the examples of this application, it is within the scope disclosed in the examples of this application. Specifically, the mass or weight described in the examples of this application may be units known in the chemical industry such as μg, mg, g, and kg.

[0059] Unless otherwise specified, the temperature parameters in this application allow for both constant temperature treatment and temperature fluctuations within a certain temperature range. It should be understood that the constant temperature treatment allows for temperature fluctuations within the accuracy range of instrument control. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are permitted.

[0060] In this application, the term "room temperature" or "normal temperature" generally refers to 4°C to 35°C, for example, 20°C ± 5°C. In some embodiments of this application, "room temperature" or "normal temperature" refers to 10°C to 30°C. In some embodiments of this application, "room temperature" or "normal temperature" refers to 20°C to 30°C.

[0061] In this application, when referring to a data range, if the unit is only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 3~5h means that the units of the left endpoint "3" and the right endpoint "5" are both h (hours).

[0062] As used herein, the term "hydrocarbon" or "hydrocarbon compound" refers to a compound composed of carbon atoms and hydrogen atoms.

[0063] Herein, the term "aromatic hydrocarbon" refers to a hydrocarbon compound having aromaticity, which includes a ring structure having aromaticity in its structure and thus has an aromatic ring.

[0064] Herein, the term "aliphatic hydrocarbon" refers to a hydrocarbon compound that does not have aromaticity, and may also be referred to as "non-aromatic hydrocarbon".

[0065] As used herein, the term "alkyl" refers to a monovalent residue formed by the loss of one hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C 1-6"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, which can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl at each occurrence. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl -1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3 -methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-CH(CH3)2CH2CH 2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3.

[0066] As used herein, the term "cycloalkyl" refers to a monovalent residue formed by a non-aromatic hydrocarbon (which may be a saturated hydrocarbon or an unsaturated hydrocarbon) containing a ring structure losing a hydrogen atom on the ring, i.e., forming a monovalent attachment site directly on the ring. Phrases containing this term, such as "C 3-6 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which may be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl or C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl Cyclobutyl Cyclopentyl Cyclohexyl Cyclohexenyl (including but not limited to ).

[0067] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, which is a monovalent residue formed by a saturated hydrocarbon containing a ring structure losing a hydrogen atom on the ring, i.e., forming a monovalent attachment site directly on the ring. Phrases containing this term, such as "C 3-6 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which can be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl or C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl Cyclobutyl Cyclopentyl Cyclohexyl

[0068] As used herein, the term "heterocycloalkyl" refers to a monovalent group in which at least one ring-membering atom in a cycloalkyl group is replaced by a heteroatom, and at least one carbon atom remains in the ring-membering atom. Phrases containing this term, such as "C 3-6 "Heterocycloalkyl" refers to a heterocycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which is independently C3 heterocycloalkyl, C4 heterocycloalkyl, C5 heterocycloalkyl or C6 heterocycloalkyl. Suitable examples of ring structures in heterocycloalkyl groups include tetrahydrofuran ring Tetrahydrofuran ring

[0069] In the present application, the term "heteroatom" refers to an atom that is not hydrogen and not carbon, such as an oxygen atom (O), a nitrogen atom (N), a sulfur atom (S), a phosphorus atom (P), chlorine (Cl), bromine (Br), iodine (I), etc.

[0070] As used herein, the term "alkoxy" refers to a group having the structure "alkyl-O-," i.e., an alkyl group as defined above attached to an adjacent group via an oxygen atom. Phrases containing this term, for example, "C1-6 alkoxy," refer to an alkyl moiety containing 1 to 6 carbon atoms, each occurrence of which may be independently C1 alkoxy, C4 alkoxy, C5 alkoxy, or C6 alkoxy. Suitable examples include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt), and tert-butoxy (-OC(CH3)3 or -OtBu).

[0071] Herein, the term "divalent heterocycloalkyl" refers to a divalent residue having two monovalent radical centers derived from a heterocycloalkyl group which loses a hydrogen atom on the ring. Phrases containing this term, for example, "divalent C 5-6"Heterocycloalkyl" refers to a divalent heterocycloalkyl group containing 5 to 6 carbon atoms, which can be independently a divalent C5 heterocycloalkyl group or a divalent C6 heterocycloalkyl group at each occurrence. Suitable examples include, but are not limited to, divalent heterocycloalkyl groups derived from the following heterocycloalkyl groups: tetrahydrofuranyl, tetrahydropyranyl. Specific examples of divalent heterocycloalkyl groups include wait.

[0072] In the present application, unless otherwise specified, "carbocycle" refers to a ring in which all the ring atoms are carbon atoms.

[0073] After a large number of experimental explorations, the inventors of the present application unexpectedly discovered a class of compounds represented by formula (I), especially triterpene derivatives, which have high bactericidal activity against some antibiotic-resistant strains. In addition, they also have broad-spectrum antibacterial activity and have strong killing effects on a variety of common pathogenic bacteria. Specifically, the triterpene derivatives represented by formula (I) have high bactericidal activity against at least one of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and linezolid-resistant enterococci. In addition, the triterpene derivatives of formula (I) also have strong killing effects on one, multiple or all of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic streptococci, beta-hemolytic streptococci, Enterococcus faecalis, vancomycin-resistant enterococci, linezolid-resistant enterococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

[0074] The present invention provides a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof. Formula (I) is:

[0075] In formula (I), Carbon-carbon double bond or carbon-carbon single bond and A1 and A2 each include a ring-forming carbon atom; The H atoms on the two ring carbon atoms in are not substituted. The H on the ring-forming carbon atom of A1 is unsubstituted and the H on the ring-forming carbon atom of A2 is substituted with a substituent; R8 is a chemical group having 5 to 20 carbon atoms; R2 and R3 are each a monovalent group, or they are linked to adjacent carbon atoms to form a six-membered carbon ring, which may be substituted or unsubstituted. The substituent to which the ring-forming carbon atom of A2 is linked may be denoted as R1, which is a monovalent group and may be a substituted or unsubstituted pyranose ring glycoside or a substituted or unsubstituted furose ring glycoside.

[0076] when When it is a carbon-carbon double bond, A1 is -CH=; when When it is a carbon-carbon single bond, A1 is a methylene group (-CH2-).

[0077] when When it is a carbon-carbon double bond, A2 is =CH-; when When it is a carbon-carbon single bond, A2 is a methylene group substituted by R1 (-CHR1-).

[0078] In the present application, "pharmaceutically acceptable salt" refers to a salt formed by a given compound with an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts.

[0079] In this application, "solvate" refers to a given compound or its salt further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In some embodiments, the solvent is water and the solvate is a hydrate.

[0080] In some embodiments, in the triterpene derivative represented by formula (I), is -CH=CH- or -CH2-CHR1-, R1 is a substituted or unsubstituted pyranose ring type glycosyl or a substituted or unsubstituted furanose ring type glycosyl, R8 is a group having 5 to 20 carbon atoms, R2 and R3 are each a monovalent group, or are connected to each other and adjacent carbon atoms to form a six-membered carbocyclic ring, and the six-membered carbocyclic ring may be substituted or unsubstituted.

[0081] In some embodiments, the ring-forming carbon atoms in A1 and A2 may each independently be bonded only to hydrogen atoms.

[0082] In other embodiments, the H on the ring-forming carbon atom in A1 is unsubstituted, and the ring-forming carbon atom in A2 is attached to a substituent, which can be denoted as R1. R1 can be a substituted or unsubstituted pyranosyl group or a substituted or unsubstituted furanosyl group, wherein the H in any hydroxyl group (-OH) in the pyranosyl group or the furanosyl group can be substituted with an acetyl group, thereby acetylating the hydroxyl group to form CH3C(=O)O-.

[0083] In some embodiments, the attachment sites in the pyranose ring and furanose ring are located at the hydroxyl groups of their respective acetal structures, such as the * position in -CO-CH(O-*)-C, and the carbon atoms at both ends are ring-forming carbon atoms, as non-limiting examples. wait.

[0084] In some embodiments, It is -CH=CH- or -CH2-CHR1-.

[0085] In some embodiments, It is -CH=CH-.

[0086] In some embodiments, It is -CH2-CHR1-.

[0087] In some embodiments, R1 is selected from any one of a pyranosyl group, a pyranosyl group in which one -OH group is acetylated, a furanosyl group, and a furanosyl group in which one -OH group is acetylated.

[0088] In some embodiments, R1 is a pyranosyl group or a furanosyl group.

[0089] In some embodiments, R1 is any one of arabinofuranosyl, arabinofuranosyl with one -OH acetylated, arabinopyranosyl, arabinopyranosyl with one -OH acetylated, rhamnopyranosyl, and rhamnopyranosyl with one -OH acetylated.

[0090] In some embodiments, R1 is arabinofuranosyl, arabinopyranosyl, or rhamnopyranosyl.

[0091] Non-limiting examples of arabinofuranosyl groups include

[0092] Non-limiting examples of arabinopyranosyl groups include

[0093] Non-limiting examples of rhamnopyranosyl groups include

[0094] In some embodiments, R1 is selected from and any of the foregoing groups wherein one -OH group is acetylated.

[0095] In some embodiments, R1 is

[0096] In some embodiments, R1 is selected from Any of

[0097] In some embodiments, R1 is arabinopyranosyl or rhamnopyranosyl.

[0098] In some embodiments, R1 is any one of α-L-arabinopyranosyl, α-L-rhamnopyranosyl, β-D-rhamnopyranosyl, and any of the foregoing groups in which one -OH group is acetylated.

[0099] In some embodiments, R1 is α-L-arabinopyranosyl, α-L-rhamnopyranosyl, or β-D-rhamnopyranosyl.

[0100] In some embodiments, R1 is and any of the foregoing groups wherein one -OH group is acetylated.

[0101] In some embodiments, R1 is

[0102] In some embodiments, R1 is

[0103] In some embodiments, R1 is

[0104] In the triterpene derivative of formula (I), R8 is a chemical group having 5 to 20 carbon atoms, in some embodiments, a chemical group having 5 to 13 carbon atoms, and further a chemical group having 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms. In some embodiments, R8 is selected from:

[0105] Among them, R a and R b can be independently selected from H, hydroxyl (-OH), substituted or unsubstituted alkyl (alkyl can be C 1-6 Alkyl), substituted or unsubstituted alkoxy (alkoxy can be C 1-6 Alkyl-O-), substituted or unsubstituted cycloalkyloxy (cycloalkyloxy may be C 3-6 Cycloalkyl-O-), substituted or unsubstituted heterocycloalkyloxy (heterocycloalkyloxy may be C 3-6 Heterocycloalkyl-O-); R c Any one independently selected from trifluoroacetyl, trichloroacetyl and tribromoacetyl.

[0106] In the definition of R8, among the substituted alkyl, substituted alkoxy, substituted cycloalkyloxy and substituted heterocycloalkyloxy, the alkyl group (such as C 1-6 Alkyl), alkoxy (such as C 1-6 Alkyl-O-), cycloalkyloxy (such as C 3-6 Cycloalkyl-O-) and heterocycloalkyloxy (such as C 3-6 The H on the heterocycloalkyl-O-) is independently substituted by one or more substituents Q3, any Q3 is independently selected from -OH, C 1-3 Alkyl (such as methyl, ethyl), C 1-3 Alkoxy (ie C 1-3 alkyl-O, such as methoxy, ethoxy) and halo (such as fluoro (-F), chloro (-Cl), bromo (-Br)).

[0107] In the definition of R8, "heterocycloalkyl (such as C 3-6 The ring atoms in the "heterocycloalkyl)" include heteroatoms X3, which may be selected from O and N, and may further be O. This definition applies to independently described heterocycloalkyls (such as C 3-6 Heterocycloalkyl), also applies to heterocycloalkyloxy (such as heterocycloalkyl-O-, further such as C 3-6 heterocycloalkyl-O-).

[0108] In the definition of R8, heterocycloalkyl (such as C 3-6 The number of the heteroatom X3 in the heterocycloalkyl group (such as C 3-6 The number of the heteroatom X3 in the heterocycloalkyl group is 1.

[0109] In this application, unless otherwise specified, the “C 1-6 "Alkyl" can independently be C 1-5 Alkyl, further optionally C 1-4 Alkyl, further optionally C 1-3 Alkyl. Any occurrence of "C 1-6 "Alkyl" may be independently selected from C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl. 1-6 "Alkyl" can be independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In some embodiments, C 1-6 The alkyl group may be methyl or ethyl. 1-6 The alkyl group may be a methyl group.

[0110] In this application, unless otherwise specified, the “C 3-6 The cycloalkyl group may be independently C 3-5 Cycloalkyl, further optionally C 3-4 Cycloalkyl, further optionally C3 cycloalkyl. 3-6 "Cycloalkyl" may be independently selected from C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl and C6 cycloalkyl. Any occurrence of "C 3-6 The "cycloalkyl" group may be independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0111] In this application, unless otherwise specified, the “C 3-6 "Heterocycloalkyl" can be independently C 3-5 Heterocycloalkyl, further optionally C 3-4 Heterocycloalkyl, further optionally C3 heterocycloalkyl.3-6 "Heterocycloalkyl" may be independently selected from C3 heterocycloalkyl, C4 heterocycloalkyl, C5 heterocycloalkyl and C6 heterocycloalkyl. 3-6 The ring structure of "heterocycloalkyl" can be independently selected from: ethylene oxide ring Tetrahydrofuran ring and tetrahydropyran ring The corresponding heterocycloalkyl groups are oxiranyl, tetrahydrofuranyl and tetrahydropyranyl.

[0112] In some embodiments, in R8, R a and R b are independently H, -OH, C 1-3 Alkyl-O-, pyranosyl or furanosyl.

[0113] In some embodiments, in R8, R a and R b are each independently H, -OH, methoxy or α-L-arabinopyranosyl.

[0114] In some embodiments, in R8, R a and R b are each independently H, -OH or methoxy.

[0115] In some embodiments, R a is -OH or pyranose ring type sugar group, further can be -OH or arabinopyranose group, further can be -OH or In some embodiments, R a In some embodiments, R a It is a pyranose ring glycosyl, further it can be an arabinopyranose group, further it can be

[0116] In some embodiments, R b In some embodiments, R b In some embodiments, R b It is a methoxy group.

[0117] In some embodiments, R8 is R c Any one independently selected from trifluoroacetyl, trichloroacetyl and tribromoacetyl.

[0118] In some embodiments, R8 is R a for

[0119] In some embodiments, R8 is

[0120] In the triterpene derivative of formula (I), R2 and R3 may be monovalent groups respectively, or they may be connected to each other and to adjacent carbon atoms to form a six-membered carbon ring, and the six-membered carbon ring may be substituted or unsubstituted.

[0121] In some embodiments, R2 is -(CH2)2-C(=O)-O-R4, and R3 is -CH(=CH2)-CH3.

[0122] R4 can be selected from H, substituted or unsubstituted alkyl (alkyl can be C 1-6 Alkyl), substituted or unsubstituted cycloalkyl (cycloalkyl can be C 3-6 Cycloalkyl), substituted or unsubstituted heterocycloalkyl (heterocycloalkyl may be C 3-6 Heterocycloalkyl) and substituted or unsubstituted phenylalkyl (alkyl may be C 1-6 alkyl); wherein, heterocycloalkyl (such as C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, which can be selected from O and N, and can further be O. In the definition of R4, heterocycloalkyl groups (such as C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group (such as C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is 1.

[0123] In the definition of R4, in the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl can be independently substituted by one or more Q1, any Q1 is independently selected from -F, -Cl, -Br, -NH2, -NO2, acetyl (CH3C(=O)-), acetoxymethyl (CH3C(=O)-O-CH2-), C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted -[O-divalent C 5-6 heterocycloalkyl] n -OH; n is an integer, which can be 0 to 5, further 0 to 4, and further 0 to 3, for example, 0, 1, 2, 3, 4 or 5.

[0124] In some embodiments, in the definition of R4, among the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl groups can be independently substituted by one or more Q1, any one of which is independently selected from -OH, -F, -Cl, -Br, -NH2, -NO2, acetyl (CH3C(=O)-), acetoxymethyl (CH3C(=O)-O-CH2-), C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted -[O-divalent C 5-6 heterocycloalkyl] n -OH; n is an integer, which can be 1 to 5, further 1 to 4, and further 1 to 3, for example, 1, 2, 3, 4 or 5.

[0125] In some embodiments, in the definition of R4, substituted -[O-divalent C 5-6 heterocycloalkyl] n -OH in the divalent C 5-6 The H in the heterocycloalkyl group is substituted by one or more Q2, any one of which can be independently an alkyl group (optionally C 1-3 The alkyl group may further be -CH3) or -OH. The number of the alkyl group and -OH in all Q2 may be 1 to 4, and further may be 1 to 3, for example 1, 2, 3 or 4.

[0126] In the definition of R4, divalent C 5-6 The ring atoms in the heterocycloalkyl group include a heteroatom X2, and the heteroatom X2 may be selected from O and N, and may further be O.

[0127] In the definition of Q1, divalent C 5-6 The number of heteroatoms X2 in the heterocycloalkyl group may be one or more, for example, 1 or 2; in some embodiments, the divalent C 5-6 The number of the heteroatom X2 in the heterocycloalkyl group is 1.

[0128] In some embodiments, in the definition of R4, any Q1 is independently selected from -OH, -F, -Cl, -Br, -NH2, -NO2, acetyl, acetoxymethyl, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted-[OZ] n -OH, wherein -OZ- is a divalent pyranose ring glycosyl or a divalent furanose ring glycosyl, Z contains -OH, and n is 1, 2, 3, 4 or 5. When n is greater than 1, adjacent -OZ- are connected by a glycosidic bond.

[0129] In some embodiments, R4 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl or phenyl C 1-6 Alkyl; wherein, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 are selected from O and N, C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is one or two.

[0130] In some embodiments, R4 is H, methyl, ethyl, or benzyl.

[0131] In some embodiments, "substituted or unsubstituted -[O-divalent C 5-6 heterocycloalkyl] n -OH" can also be selected as -[OC 5-6 Heterocycloalkyl (OH) 0-4 (CH3) 0-4 ] n -OH, n is defined as above. 5-6 heterocycloalkyl] n -OH in any of the "C 5-6 The "heterocycloalkyl" is a divalent group, wherein the H can be independently substituted by 0 to 4 -OH groups, and can also be independently substituted by 0 to 4 methyl groups.

[0132] In some embodiments, R2 and R3 are connected to each other and adjacent carbon atoms to form a six-membered carbocyclic ring, which may be substituted or unsubstituted. Further, the H in the six-membered carbocyclic ring may be substituted by one or more groups selected from the group consisting of: 1-3 Alkyl (such as methyl, ethyl) and R7-O-.

[0133] R7 may be the same as or different from R4.

[0134] In some embodiments, R7 can be selected from H, substituted or unsubstituted alkyl (alkyl can be C 1-6 Alkyl), substituted or unsubstituted cycloalkyl (cycloalkyl can be C 3-6 Cycloalkyl) and substituted or unsubstituted heterocycloalkyl (heterocycloalkyl may be C 3-6 Heterocycloalkyl) and substituted or unsubstituted phenylalkyl (alkyl may be C 1-6 alkyl); wherein, heterocycloalkyl (such as C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, which can be selected from O and N, and can further be O. In the definition of R7, heterocycloalkyl (such as C 3-6The number of the heteroatom X1 in the heterocycloalkyl group (such as C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is 1.

[0135] In the definition of R7, in the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl can be independently substituted by one or more Q1, any Q1 is independently selected from -F, -Cl, -Br, -NH2, -NO2, acetyl (CH3C(=O)-), acetoxymethyl (CH3C(=O)-O-CH2-), C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted -[O-divalent C 5-6 heterocycloalkyl] n -OH; n is an integer, which can be 0 to 5, further 0 to 4, and further 0 to 3, for example, 0, 1, 2, 3, 4 or 5.

[0136] In some embodiments, in the definition of R7, in the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl groups is independently substituted by one or more Q1, any Q1 is independently selected from -OH, -F, -Cl, -Br, -NH2, -NO2, acetyl (CH3C(=O)-), acetoxymethyl (CH3C(=O)-O-CH2-), C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, substituted or unsubstituted-[O-divalent C 5-6 heterocycloalkyl] n -OH; n is an integer, n can be selected from 1 to 5, further can be selected from 1 to 4, further can be selected from 1 to 3, for example, 1, 2, 3, 4 or 5.

[0137] In some embodiments, in the definition of R7, substituted -[O-divalent C 5-6 heterocycloalkyl] n -OH in the divalent C 5-6 The H in the heterocycloalkyl group may be substituted by one or more Q2, any one of which is independently an alkyl group (optionally C 1-3 The alkyl group may further be -CH3) or -OH. The number of the alkyl group and -OH in all Q2 may be 1 to 4, and further may be 1 to 3, for example 1, 2, 3 or 4.

[0138] In the definition of R7, divalent C5-6 The ring atoms in the heterocycloalkyl group include a heteroatom X2, and the heteroatom X2 may be selected from O and N, and may further be O.

[0139] In the definition of R7 and Q1, the divalent C 5-6 The number of heteroatoms X2 in the heterocycloalkyl group may be one or more, for example, 1 or 2; in some embodiments, the divalent C 5-6 The number of the heteroatom X2 in the heterocycloalkyl group is 1.

[0140] In some embodiments, in the definition of R7, any Q1 is independently selected from -OH, -F, -Cl, -Br, -NH2, -NO2, acetyl, acetoxymethyl, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted-[OZ] n -OH, wherein -OZ- is a divalent pyranose ring glycosyl or a divalent furanose ring glycosyl, Z contains -OH, and n is 1, 2, 3, 4 or 5. When n is greater than 1, adjacent -OZ- are connected by a glycosidic bond.

[0141] In some embodiments, any R7 is independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocycloalkyl and substituted or unsubstituted phenyl C 1-6 Alkyl; wherein, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 are selected from O and N, C 3-6 The number of the heteroatoms X1 in the heterocycloalkyl group is one or more, for example, one or two; wherein the substituted C 1-6 Alkyl, substituted C 3-6 Cycloalkyl, substituted C 3-6 Heterocycloalkyl-substituted phenyl C 1-6 In the alkyl group, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and phenyl C 1-6 The H in the alkyl group is independently substituted by one or more Q1, and any Q1 is independently selected from -OH, -F, -Cl, -Br, -NH2, -NO2, acetyl, acetoxymethyl, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted-[OZ] n-OH, wherein -OZ- is a divalent pyranose ring glycosyl or a divalent furanose ring glycosyl, Z contains -OH, and n is 1, 2, 3, 4 or 5. When n is greater than 1, adjacent -OZ- are connected by a glycosidic bond.

[0142] In some embodiments, R7 is H, arabinopyranosyl, arabinopyranosyl with one hydroxyl group acetylated, arabinofuranosyl, arabinofuranosyl with one hydroxyl group acetylated, rhamnopyranosyl, or rhamnopyranosyl with one hydroxyl group acetylated. It can further be arabinopyranosyl, arabinopyranosyl with one hydroxyl group acetylated, arabinofuranosyl, arabinofuranosyl with one hydroxyl group acetylated, rhamnopyranosyl, or rhamnopyranosyl with one hydroxyl group acetylated.

[0143] In some embodiments, R7 is H, arabinopyranosyl, arabinofuranosyl, or rhamnopyranosyl, and may further be arabinopyranosyl, arabinofuranosyl, or rhamnopyranosyl.

[0144] In some embodiments, R7 is H, arabinofuranosyl, or rhamnopyranosyl. Further, it can be arabinofuranosyl or rhamnopyranosyl.

[0145] In some embodiments, R7 is

[0146] In some embodiments, R7 is

[0147] In some embodiments, R7 is

[0148] In some embodiments, in the triterpene derivative of formula (I), is -CH=CH- or -CH2-CHR1-;

[0149] R1 is selected from any one of a pyranose ring glycoside, a pyranose ring glycoside with one -OH acetylated, a furanose ring glycoside, and a furanose ring glycoside with one -OH acetylated; And any one of the above groups in which one -OH is acetylated; further optionally

[0150] R2 is -(CH2)2-C(=O)-O-R4, R3 is -CH(=CH2)-CH3, or R2 and R3 are both -(CR5R6)2- and R2, R3 and adjacent carbon atoms form a 6-membered saturated ring, and any R5 and any R6 are independently H, methyl or -OR7;

[0151] R4 and any one R7 are independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocycloalkyl and substituted or unsubstituted phenyl C 1-6 Alkyl; wherein, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 are selected from O and N, C 3-6 The number of heteroatoms X1 in the heterocycloalkyl group is one or more; 1-6 Alkyl, substituted C 3-6 Cycloalkyl, substituted C 3-6 Heterocycloalkyl and substituted phenyl C 1-6 In the alkyl group, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and phenyl C 1-6 The H in the alkyl group is independently substituted by one or more Q1, and any Q1 is independently selected from -F, -Cl, -Br, -NH2, -NO2, acetyl, acetoxymethyl, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, substituted or unsubstituted-[O-divalent C 5-6 heterocycloalkyl] n -OH; substituted-[O-divalent C 5-6 heterocycloalkyl] n -OH, divalent C 5-6 The H in the heterocycloalkyl group is substituted by one or more Q2, any Q2 being independently -CH3 or -OH, -CH3 and -OH being in the divalent C 5-6 The number of all Q2 in the heterocycloalkyl group is independently 1 to 4, and the divalent C 5-6 The ring atoms in the heterocycloalkyl group include heteroatoms X2, wherein the heteroatoms X2 are selected from O and N, divalent C 5-6 The number of the heteroatom X2 in the heterocycloalkyl group is one or more, and n is 0, 1, 2, 3, 4 or 5;

[0152] R8 is selected from:

[0153] where R a and R b are independently selected from H, -OH, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-O-, substituted or unsubstituted C 3-6Cycloalkyl-O- and substituted or unsubstituted C 3-6 Heterocycloalkyl-O-, wherein the substituted C 1-6 Alkyl, substituted C 1-6 Alkyl-O-, substituted C 3-6 Cycloalkyl-O- and substituted C 3-6 Heterocycloalkyl-O-, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O- and C 3-6 The H in heterocycloalkyl-O- is independently substituted by one or more Q3, any Q3 being independently selected from: -OH, methyl, ethyl, acetyl, methoxy, ethoxy, -F, -Cl and -Br; C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X3, wherein the heteroatoms X3 are selected from O and N (the heteroatoms X3 may further be O); R c Any one independently selected from trifluoroacetyl, trichloroacetyl and tribromoacetyl.

[0154] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (II) or a compound of formula (III):

[0155] R1, R2, R3, and R8 are as defined above.

[0156] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (I-a1):

[0157] wherein R1, R5, R6, R7, and R8 are as defined above.

[0158] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ia), a compound of formula (Ib), or a compound of formula (Ic);

[0159] R1, R2, R3, R4, R7 and R8 are as defined above.

[0160] Based on any suitable embodiment of the present application, in some further embodiments, any C 1-6 The alkyl groups are independently C 1-4 The alkyl group may further be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further may be methyl or ethyl, further may be methyl.

[0161] Based on any suitable embodiment of the present application, in some further embodiments, any C 3-6Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0162] Based on any suitable embodiment of the present application, in some further embodiments, any C 3-6 The heterocycloalkyl group is independently oxiranyl, tetrahydropyranyl or tetrahydrofuranyl, and can further be tetrahydropyranyl or tetrahydrofuranyl.

[0163] Based on any suitable embodiment of the present application, in some further embodiments, any divalent C 5-6 The heterocycloalkyl groups are independently divalent tetrahydropyranyl or divalent tetrahydrofuranyl.

[0164] Based on any suitable embodiment of the present application, in some further embodiments,

[0165] Any C 1-6 Alkyl is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and further optionally methyl or ethyl, and further optionally methyl;

[0166] Any C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0167] Any C 3-6 Heterocycloalkyl is independently oxiranyl, tetrahydropyranyl or tetrahydrofuranyl, and can further be tetrahydropyranyl or tetrahydrofuranyl;

[0168] Any bivalent C 5-6 The heterocycloalkyl groups are independently divalent tetrahydropyranyl or divalent tetrahydrofuranyl.

[0169] Based on any suitable embodiment of the present application, in some further embodiments, the substituted or unsubstituted C 3-6 Heterocycloalkyl is or a group in which one -OH group in any of the aforementioned groups is acetylated.

[0170] Based on any suitable embodiment of the present application, in some further embodiments, the substituted or unsubstituted C 3-6 Heterocycloalkyl is

[0171] Based on any suitable embodiment of the present application, in some further embodiments, the substituted or unsubstituted C 3-6 Heterocycloalkyl is selected from:

[0172] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ia) or a compound of formula (Ic), and R1 is a pyranosyl or furanosyl ring glycosyl. It can further be an arabinopyranosyl or rhamnopyranosyl. It can further be

[0173] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ib) or a compound of formula (Ic), R4 is H, C 1-3 Alkyl or phenyl C 1-6 Further, R4 can be H.

[0174] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); in R8, R a and R b are each independently H, -OH or methoxy.

[0175] In some embodiments, in compound (Ia), R1 may be as defined above, and R1 may be optionally R7 can be as defined above, R7 can be optionally R8 is Among them, R c In some embodiments, R8 is independently selected from any one of trifluoroacetyl, trichloroacetyl and tribromoacetyl;

[0176] In some embodiments, in compound (Ib), R4 is H, methyl, ethyl or benzyl (further optionally H), and R8 is R a It can be defined as above, R a Optional

[0177] In some embodiments, in compound (Ic), R1 is R4 is H, methyl, ethyl or benzyl, R8 is

[0178] In some embodiments, the triterpene derivative of formula (I) is compound (Ic), R1 is arabinopyranosyl or rhamnopyranosyl, and R1 can be R4 is H or benzyl, R8 is

[0179] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); the compound of formula (Ic) satisfies one, two, or three of the following characteristics:

[0180] R1 is a pyranose ring glycosyl or a furanose ring glycosyl (R1 can be optionally arabinopyranose or rhamnopyranose);

[0181] R8 is

[0182] R4 is H or benzyl.

[0183] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); R1 is arabinopyranosyl or rhamnopyranosyl; R8 is R4 is H or benzyl.

[0184] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); the compound of formula (Ic) satisfies one, two, or three of the following characteristics:

[0185] R1 is a pyranose ring glycosyl or a furanose ring glycosyl (R1 can be optionally arabinopyranose or rhamnopyranose);

[0186] R8 is

[0187] R4 is H or benzyl.

[0188] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); R1 is arabinopyranosyl or rhamnopyranosyl; R8 is R4 is H or benzyl.

[0189] In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); R8 is R4 is H.

[0190] In some embodiments, the triterpene derivative of formula (I) is any of the following compounds:

[0191] Compound C1: is a compound of formula (Ia), wherein R1 is R7 is R8 is

[0192] Compound C2: is a compound of formula (Ia), wherein R1 is R7 is R8 is

[0193] Compound C3: is a compound of formula (Ib), wherein R4 is H, R8 is R a for

[0194] C4 compound: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is

[0195] Compound C5: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is R b It is a methoxy group.

[0196] Compound C6: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is R b It is a methoxy group.

[0197] Compound C7: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is R a For OH.

[0198] Compound C8: is a compound of formula (Ic), wherein R1 is (Right now ), R4 is H, R8 is

[0199] Compound C9: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is R b For OH.

[0200] Compound C10: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is R b For OH.

[0201] Compound C11: is a compound of formula (Ic), wherein R1 is R4 is benzyl, R8 is

[0202] C12 compound: is a compound of formula (Ic), wherein R1 is R4 is methyl, R8 is

[0203] Compound C13: is a compound of formula (Ic), wherein R1 is R4 is ethyl, R8 is

[0204] Compound C14: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is

[0205] Compound C15: is a compound of formula (Ic), wherein R1 is R4 is H, R8 is

[0206] Compound C16: a compound of formula (Ia), wherein R1 is R7 is R8 is

[0207] C17 compound: is a compound of formula (Ia), wherein R1 is R7 is R8 is

[0208] C18 compound: is a compound of formula (Ib), wherein R4 is benzyl, R8 is R a for

[0209] Compound C19: a compound of formula (Ib), wherein R4 is methyl, R8 is R a for

[0210] The triterpene derivatives of formula (I) can be isolated and purified from the natural plant Cyclocarya paliurus (e.g., compounds C1-C10), or can be obtained by structural optimization of the isolated triterpene derivatives (e.g., compounds C11-C19). The triterpene derivatives of formula (I) are active compounds with a broader antibacterial spectrum, higher efficacy, better drugability, and better safety, and can be used in the preparation of antibacterial drugs and antibacterial agents, and can be applied to the treatment of bacterial infections (including but not limited to drug-resistant bacterial infections). Pharmaceutically acceptable salts of the triterpene derivatives of formula (I) can be prepared using conventional salt-forming methods in the art, such as, but not limited to, cooling crystallization, antisolvent methods, and the like.

[0211] Traditionally, Cyclocarya paliurus is believed to have the effects of clearing heat and relieving summer heat, lowering blood sugar, and lowering blood pressure. Recent research has focused on the hypoglycemic pharmacology and the underlying substance of its efficacy. In this application, a specific separation and purification method is used to obtain triterpene derivatives from Cyclocarya paliurus leaf extract, and further derivatize new triterpene derivatives. The separation and purification method used in this application has a higher extraction efficiency.

[0212] After extensive experimental exploration, the applicant of this application unexpectedly discovered that triterpene derivatives of formula (I) have strong killing effects on a variety of common pathogenic bacteria, such as Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Escherichia coli, Enterococcus faecalis, vancomycin-resistant Enterococci, Pseudomonas aeruginosa, Mycobacterium abscessus, Klebsiella pneumoniae, and Helicobacter pylori. Triterpene derivatives of formula (I) also have high bactericidal activity against some antibiotic-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci, and linezolid-resistant Enterococci.

[0213] The minimum inhibitory concentration (MIC) of the triterpene derivative of formula (I) for one or more of the above-mentioned bacteria can reach less than 150 μg / mL, further can reach less than or equal to 75 μg / mL, further can reach less than or equal to 37.5 μg / mL, and further can reach less than or equal to 9.375 μg / mL.

[0214] As a non-limiting example, for example, the MIC of compound C8 against alpha-hemolytic streptococci, beta-hemolytic streptococci, and Streptococcus pneumoniae may meet ≤9.375 μg / mL, the MIC against Staphylococcus aureus, MRSA, Staphylococcus epidermidis, and Escherichia coli may meet ≤18.75 μg / mL, the MIC against Staphylococcus saprophyticus may meet ≤37.5 μg / mL, the MIC against Enterococcus faecalis, vancomycin-resistant enterococci, and linezolid-resistant enterococci may meet ≤75 μg / mL, and the MIC against Pseudomonas aeruginosa, Mycobacterium abscessus, Klebsiella pneumoniae, and Helicobacter pylori may meet ≤150 μg / mL.

[0215] In some embodiments, Compound C8 and Compound C11 can be used to target Streptococci (such as group A / B hemolytic Streptococci and Streptococcus pneumoniae) and Staphylococci (such as methicillin-resistant / sensitive Staphylococcus aureus and Staphylococcus epidermidis). They can be used to treat, but are not limited to, skin and soft tissue infections, respiratory tract infections, heart valve infections, and bone and joint infections. In some embodiments, Compound C11 has a slightly stronger killing effect on Staphylococci than Compound C8.

[0216] In some embodiments, compound C14 has a killing effect on streptococci (such as alpha / beta hemolytic streptococci and streptococci pneumoniae) and staphylococci (such as methicillin-resistant / sensitive Staphylococcus aureus and Staphylococcus epidermidis), and can also have a killing effect on Bacillus (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Mycobacterium abscessus, Helicobacter pylori, etc.). Compound C14 has a stronger killing effect on E. coli than compounds C8 and C11. In addition, compound C14 also has a certain killing effect on Enterococcus faecalis, vancomycin-resistant enterococci, and linezolid-resistant enterococci. Compound C14 can also be used for skin and soft tissue infections, respiratory tract infections, heart valve infections, and bone and joint infections. In addition, it may also be suitable for digestive tract infections, bacteremia, etc.

[0217] In some embodiments, compound C15 has a good effect on Streptococcus, Staphylococcus aureus, Bacillus, and Enterococcus. Based on the above application examples of compound C14, compound C15 can also be used for urinary tract infections.

[0218] In some embodiments, relative to Lactobacillus acidophilus, the triterpene derivatives of formula (I) exhibit certain selectivity in their antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci and linezolid-resistant enterococci, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

[0219] In this application, MIC (Minimal Inhibitory Concentration) can be used to characterize antibacterial activity. The lower the MIC value, the lower the effective antibacterial concentration and the stronger the antibacterial efficacy. The triterpene derivatives of formula (I) in this application can achieve antibacterial effects by targeting FtsZ.

[0220] The bacterial division Z ring, a ring-shaped structure formed by the filamentous temperature-sensitive mutant Z (FtsZ) protein at the site of cell division, is essential for bacterial survival and proliferation. Because it is present in most bacterial species, highly conserved, and crucial for cell division, cell wall formation, cell morphology, and structural stability, it is a potential target for new antibiotics. Although a few compounds targeting FtsZ have been successfully synthesized, such as PC190723, no antibacterial drugs targeting FtsZ have been marketed globally due to poor drugability and high toxicity.

[0221] The triterpene derivatives of formula (I) provided in the present application target FtsZ, occupy the binding domain of FtsZ and its active substrate guanosine triphosphate (GTP), hinder the binding of FtsZ and GTP, lead to GTP hydrolysis disorder, block the formation of Z ring, and make the cells after nucleic acid replication unable to complete division, and eventually the bacteria rupture and die. Therefore, the triterpene derivatives of formula (I) that can bind to the GTP site have antibacterial effects, and the antibacterial efficacy is positively correlated with its binding force. As a drug target that has not yet been clinically applied, bacteria have no resistance to drugs targeting FtsZ. The triterpene derivatives of formula (I) have the effect of treating drug-resistant bacterial infections.

[0222] Mammalian cells do not secrete FtsZ. Therefore, it is believed that the triterpene derivatives of formula (I) have no known toxic side effects in humans. In addition, the triterpene derivatives of formula (I) are derived from natural plants that have both edible and medicinal properties, and have the advantage of good drugability.

[0223] The top and bottom structures of the FtsZ protein have significant geometric complementarity. In the multimeric state, a wide hydrophobic interaction region is formed between the bottom of the FtsZ protein at the top (C-terminal domain) and the top of the FtsZ protein at the bottom (N-terminal domain). The GTP binding domain in the FtsZ structure is composed of 85 carbon atoms, 24 nitrogen atoms and 27 oxygen atoms, forming a pocket-like structure. The pocket volume is Has a surface area of Depth up to Theoretically, FtsZ has 17 hydrogen bond donor units and 34 acceptor units, with 20 hydrophobic binding sites. The hydrophilic / hydrophobic ratio is 0.28. A schematic diagram of the FtsZ binding pocket can be found in Figure 3, where the light-colored portion represents the binding pocket region.

[0224] Molecular docking revealed that the binding site of the triterpene derivative of formula (I) may be in the GTP binding domain between the N-terminus and the H7 helix of FtsZ. Its binding mechanism may be similar to the reported crystal structure of the FtsZ-GTP complex (PDB ID: 5MN5).

[0225] Taking compounds C8 and C11 as examples, Figures 1A-1B and 2A-2B illustrate the binding modes of compounds C8 and C11 with FtsZ, respectively. Figure 1A is a visualization of the docking of compound C8 with FtsZ, and Figure 1B is a surface diagram of the interaction between compound C8 and FtsZ. Figure 2A is a visualization of the docking of compound C11 with FtsZ, and Figure 2B is a surface diagram of the interaction between compound C11 and FtsZ.

[0226] See Figures 1A-1B and Table 4. Molecular docking revealed that compound C8 deeply inserts into the GTP-binding pocket of FtsZ, forming hydrogen bonds with amino acid residues Gly108, Thy109, Glu139, and Asn166. It also binds to amino acid residues Asp46, Pro135, and Phe183 via hydrophobic interactions, and to amino acid residue Arg143 via ionic bonds. Analysis revealed a docking index of -5.593 for compound C8 with FtsZ, comparable to the docking index of -5.612 for the natural ligand GTP. It is speculated that compound C8 competitively binds to the GTP-binding site of FtsZ, resulting in the loss of GTPase activity and the inability of FtsZ to catalyze Z-ring formation, ultimately leading to bacterial death.

[0227] PC190723 is the most studied compound targeting FtsZ. Its binding site is located in the gap formed by the H7 helix and the C-terminal domain, rather than directly interacting with the GTP-binding domain of FtsZ. However, upon binding to FtsZ, compounds C8 and PC19023 inhibited FtsZ's GTPase activity. The triterpene derivatives of formula (Ib) and formula (Ic) differ from the triterpene derivative of formula (Ia) in that the triterpene derivatives of formula (Ib) and formula (Ic) are ring-opened tetracyclic triterpene derivatives, while the triterpene derivative of formula (Ia) is a tetracyclic triterpene derivative with a complete structure. Among the compounds contained in the plant Cyclocarya paliurus, ring-opened tetracyclic triterpene derivatives typically have carboxyl groups, which contain active hydrogens and are prone to hydrogen bonding, potentially helping to stabilize this binding and achieve a better antibacterial effect.

[0228] It has been verified that the triterpene derivatives of formula (I) provided in the present application have good FtsZ binding ability, which can be seen in the following Examples.

[0229] In yet another aspect of the present application, a method for preparing a triterpene derivative of formula (I) is provided.

[0230] In some embodiments, some triterpene derivatives are extracted from Cyclocarya paliurus, such as compounds C1 to C10.

[0231] In some embodiments, some triterpene derivatives are prepared based on triterpene derivatives extracted from Cyclocarya paliurus through one or more derivatization methods such as esterification, acylation, alkylation, double bond addition reaction, etc., such as compounds C11 to C19.

[0232] This application provides a method for isolating and purifying triterpene derivatives from Cyclocarya paliurus, and also provides a method for modifying the extracted triterpene derivatives through chemical reactions. Method 1 or Method 2 below can be used.

[0233] Method 1: Isolation and purification of triterpene derivatives from Cyclocarya paliurus: Shade-dried Cyclocarya paliurus leaves are subjected to two reflux extractions using 10 times their weight of ethanol. The combined filtrates are concentrated to dryness, mixed with silica gel, and then dry-applied to a silica gel column for gradient elution to obtain the compound. The elution solvent may be selected from one or more of the following: dichloromethane, methanol, water, petroleum ether, and ethyl acetate. The triterpene derivatives obtained by Method 1 may be referred to as "extract compounds."

[0234] Method 2: Based on the triterpene derivative obtained in Method 1, triterpene derivatives with other structures can be obtained through conventional chemical reactions such as esterification, addition, acylation, and alkylation. If necessary, a suitable hydroxyl protecting agent can be used to protect the hydroxyl group during the reaction.

[0235] The above-mentioned reagents for group modification of the extract compounds can be selected from one or more of the following: acetic anhydride, benzoyl chloride, trifluoroacetyl ester, benzyl ether, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, sec-butanol, isobutanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, acetyl chloride, dimethyl sulfate and benzyl chloride.

[0236] The triterpene derivatives of formula (I) can also be prepared by reacting other triterpene compounds or triterpene derivatives.

[0237] The above-mentioned compounds provided in this application can be derived from natural plants. They not only have high antibacterial efficacy and a broad antibacterial spectrum, but also have obvious inhibitory and killing activities against a variety of antibiotic-resistant strains. The effective dose MIC can reach the antibacterial level of some currently known synthetic antibiotics.

[0238] The present application also provides an antibacterial composition comprising a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0239] The present application also provides an embodiment of the use of a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of an antibacterial composition.

[0240] In the present application, an "antimicrobial composition" refers to a composition having an antimicrobial effect, which contains, in addition to an antimicrobial component, a second component, which may be an antimicrobial component or a non-antimicrobial component.

[0241] In this application, "antimicrobial ingredient" refers to an ingredient with antimicrobial effect; "non-antimicrobial ingredient" refers to an ingredient without antimicrobial effect. Non-antimicrobial ingredients may have other physiological and / or pharmacological functions and may also be excipients.

[0242] In the present application, whether or not a substance has an "antibacterial effect" refers to whether or not it has a killing or inhibitory effect on bacteria.

[0243] In the present application, a "composition" may be a combination of multiple substances, and further, may be used in combination, or may be a mixture of the combination.

[0244] In this application, an "antimicrobial composition" refers to a composition that has an antimicrobial effect. This composition can be used medically, such as to treat or alleviate bacterial infections, or for non-medical purposes, such as cleaning and sterilizing everyday items, or improving the antimicrobial properties of specific products, such as in the manufacture of antimicrobial products.

[0245] In some embodiments, the triterpene derivatives of formula (I) and antibacterial compositions containing the same, in addition to pharmaceutical uses, can also be used as functional materials in daily necessities, packaging supplies, household appliances, environmental materials, building materials and coatings, etc. Non-limiting examples include antibacterial films, touch surfaces of electrical appliances, water treatment, sanitary ceramics, antibacterial coatings, etc.

[0246] In some embodiments, the triterpene derivatives of formula (I) and antibacterial compositions containing the same can also be used in oral preparations, such as mouthwashes, toothpastes, skin, mucous membrane, and lumen washes.

[0247] In some embodiments, the triterpene derivatives of formula (I) and antibacterial compositions containing the same can be used in the field of animal husbandry. For example, they can be added to animal feed for the prevention of bacterial infections, and can also be used in veterinary preparations for the treatment of bacterial infections. It should be understood that "excipients" can be selected from substances allowed to be added in relevant management specifications, and further, do not include substances prohibited from being added in relevant management specifications. Unless otherwise specified, relevant management specifications refer to the current specifications at the time of production.

[0248] The present application also provides an antibacterial drug comprising a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0249] The embodiments of the present application also provide the use of a triterpene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an antibacterial pharmaceutical composition; the antibacterial pharmaceutical composition comprises a triterpene derivative of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0250] In the present application, "antibacterial drug" and "antibacterial drug composition" refer to a pharmaceutical composition with antibacterial effect.

[0251] As used herein, "drug" includes any agent, compound, composition, or mixture that provides a pharmacological effect in vivo or in vitro, often with a beneficial effect. The scope of the pharmacological effect of a "drug" in vivo is not particularly limited and may be systemic or localized. The activity of the "drug" is not particularly limited and may be an active substance that interacts with other substances or an inert substance that does not interact.

[0252] In this application, a "pharmaceutical composition" refers to a composition that has the effect of preventing or treating a disease or condition and can be used as a medicine or can be used in medicine. In this application, a "pharmaceutical" refers to a pharmaceutical preparation that can be directly administered, which generally has a prescribed usage and dosage, consistent with the above definition.

[0253] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0254] In this application, a "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the phrase "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, isotonicity agents, and absorption delaying agents, and the like, that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to, one or more of the following: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and teff oil. olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0255] In the present application, "carrier" may include, but is not limited to, mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine ​​hydrochloride, thioglycolic acid, methionine, vitamin C, disodium ethylenediaminetetraacetic acid (disodium EDTA), sodium calcium EDTA, carbonates, acetates, phosphates of monovalent alkali metals or their aqueous solutions, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, oligofructose, dextran, glycine, starch, sucrose, dextrin (such as maltodextrin), lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinyl pyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, phospholipid materials, kaolin, talc, calcium stearate, and one or more of magnesium stearate.

[0256] It should be understood that "pharmaceutically acceptable carriers" can be selected from substances permitted by relevant regulatory standards, and further, do not include substances prohibited by relevant regulatory standards. Unless otherwise specified, relevant regulatory standards refer to the standards in effect at the time of production.

[0257] The present application also provides examples of the use of triterpene derivatives of formula (I) or pharmaceutically acceptable salts thereof in drugs for preventing and treating bacterial infections.

[0258] The present application also provides a method for treating, improving or preventing bacterial infection, comprising administering a therapeutically effective amount of a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need.

[0259] The present application also provides a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in treating, improving or preventing bacterial infection or diseases caused by bacterial infection.

[0260] In some embodiments, the disease caused by bacterial infection includes a disease caused by drug-resistant bacterial infection, and the disease caused by drug-resistant bacterial infection includes a disease caused by infection with at least one of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and linezolid-resistant Enterococcus.

[0261] In this application, "prevention and treatment" and "prevention and / or treatment" have the same meaning and can be used interchangeably. In this application, "prevention and treatment" includes aspects such as prevention, treatment, and adjuvant treatment. As used herein, "prevention and treatment" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition. "Prevention and treatment" also includes curing one or more symptoms of a disease or condition, preventing its development, or alleviating to a certain extent. Among them, as used herein, "treatment" refers to alleviating, delaying progression, attenuating, or maintaining an existing disease or condition, and treatment also includes curing one or more symptoms of a disease or condition, preventing its development, or alleviating to a certain extent.

[0262] In this application, a "subject" is an animal, which may be a mammal, and further may be a human. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including but not limited to cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice (such as rats and mice), pigs, cattle, sheep, horses, humans, etc., and may be, for example, primates, and further may be humans.

[0263] In some embodiments, the subject is a mammal.

[0264] In some embodiments, the subject may be a patient who has already suffered from a bacterial infection, or a person who is at risk of suffering from a bacterial infection, such as a person who has undergone or is about to undergo a surgical operation, a person with trauma, etc.

[0265] In some embodiments, the subject can be an animal in the animal husbandry field. As a non-limiting example, the triterpene derivatives of formula (I) and antibacterial compositions containing the same can be added to animal feed for the prevention of bacterial infection, and can also be used in veterinary preparations for the treatment of bacterial infection.

[0266] In this application, "therapeutically effective amount" refers to the amount of a pharmaceutical active ingredient that will cause a biological or medical response in an individual to a disease, disorder and / or symptom, for example, the amount of a pharmaceutical active ingredient that brings a pharmacologically positive effect to an individual, and the pharmacologically positive effect includes but is not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression or preventing disease, etc.

[0267] Administration routes may include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) injection, topical administration, and inhalation. Taking oral administration as an example, corresponding oral formulations may include, but are not limited to, oral formulations such as mouthwashes, toothpastes, and skin, mucosal, or luminal washes. Taking topical administration as an example, corresponding formulations may include creams, ointments, patches, or sprays suitable for application to the skin.

[0268] The embodiments of the present application also provide a product comprising a triterpene derivative represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0269] The embodiments of the present application also provide a method for using the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof as an antibacterial active substance, comprising adding the compound or a pharmaceutically acceptable salt or solvate thereof to a desired product or coating the surface of the product.

[0270] The embodiments of the present application also provide the use of a triterpene derivative of formula (I) or a pharmaceutically acceptable salt thereof in preparing a product, wherein the triterpene derivative of formula (I) is as defined in the first aspect of the present application.

[0271] As non-limiting examples, the products may include but are not limited to at least one of medicines, medical devices, daily necessities, cosmetics, packaging supplies, etc., and the daily necessities may include but are not limited to one or more of cleaning supplies, sanitary care products, bedding, kitchen utensils, dining utensils, toys, etc.

[0272] An embodiment of the present application also provides a disinfectant, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0273] The present application also provides a method for disinfection, comprising applying a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof to a desired target.

[0274] The present application also provides the use of the triterpene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a disinfectant.

[0275] In some embodiments, the use can be for therapeutic purposes.

[0276] In some embodiments, the applications are for non-diagnostic and therapeutic purposes. For example, the compounds can be used as reference compounds for antimicrobial drug screening, as functional materials for applications in daily necessities, packaging, household appliances, environmental materials, building materials, and coatings. They can also be used in materials or products such as antimicrobial films, touch surfaces of electrical appliances, water treatment products, sanitary ceramics, and antimicrobial coatings.

[0277] The present application also provides an FtsZ protein inhibitor, including a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0278] The present application also provides a method for inhibiting FtsZ protein, comprising contacting cells with an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0279] In some embodiments, the cell can be, for example, a bacterial cell, specifically a bacterial cell having an FtsZ protein, the bacteria including but not limited to methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and linezolid-resistant enterococci, one or more of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, vancomycin-resistant enterococci, linezolid-resistant enterococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

[0280] The present application also provides the use of the triterpene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an FtsZ protein inhibitor.

[0281] In some embodiments, the use can be for therapeutic purposes.

[0282] In some embodiments, the use is for non-diagnostic and non-therapeutic purposes.

[0283] In some embodiments, the triterpene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof has a killing effect on any one, any two or all of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and linezolid-resistant enterococci. In some embodiments, the triterpene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof also has a killing effect on one, multiple or all of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

[0284] In some embodiments, the triterpene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used in any suitable form of any of the following groups:

[0285] Preparations shown in Group A: tablets, capsules, granules, pills, ointments, solutions, suspensions, emulsions and creams;

[0286] Preparations shown in Group B: oral solution, lozenge, injection, suppository, spray, drop, patch and tube feeding preparations;

[0287] The form shown in group C: surface coating of a solid product and dopant in a solid product, wherein the solid product at least includes a plastic product.

[0288] Some specific examples are provided below.

[0289] The embodiments of the present application will be described in detail below with reference to the examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manuals or conventional conditions in this area, or according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art.

[0290] In the following specific examples, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument testing accuracy or operational accuracy are allowed.

[0291] Unless otherwise specified, "room temperature" hereinafter refers to 20-30°C, and may further be 25°C.

[0292] Unless otherwise specified, "80% ethanol" refers to a mixed solvent consisting of 80% by volume ethanol and 20% by volume water.

[0293] Unless otherwise specified, when referring to a solution, if the solvent is not specified, the solvent is water. For example, "5% hydrochloric acid" means a hydrochloric acid solution with a weight percentage of 5% HCl; "5% sodium bicarbonate" means a hydrochloric acid solution with a weight percentage of 5% sodium bicarbonate.

[0294] Unless otherwise specified, HOBt is 1-hydroxybenzotriazole, EDC is 1-ethyl-(3-dimethylaminopropyl)carbodiimide, DMAP is 4-dimethylaminopyridine, DIEA is diisopropylethanolamine, and DMSO is dimethyl sulfoxide.

[0295] 1. Preparation of Cyclocarya paliurus triterpenoid derivatives

[0296] (1) Extraction and preparation of triterpenoid derivatives 1-10 from Cyclocarya paliurus

[0297] Weigh 5 kg of room temperature dried green willow leaves, crush them and add 10 times their weight of 80% ethanol, reflux extract at 50 ° C for 1 hour, filter the residue and extract it again in the same way, combine the filtrates of the two extractions, concentrate and dry (300 g), mix with silica gel (100-200 mesh), and dry load it on a 3000 g silica gel column. Elute with dichloromethane-methanol (90%-0%) gradient, that is, gradient elution from dichloromethane: methanol volume ratio of 90%:10% to 0%:100%, the elution volume is 3 column volumes, and 6 fractions (Fr.1-6) are obtained. Fr.1 (55 g) was applied to an 800 g silica gel column and eluted with a gradient of petroleum ether-ethyl acetate (100%-20%, i.e., from a petroleum ether:ethyl acetate volume ratio of 100%:0% to 20%:80%) over 3 column volumes to obtain five fractions (Fr.1a-e). Fr.1b (2 g) was repeatedly subjected to C18 preparative chromatography with a gradient of methanol-water (20%-100%, i.e., from a methanol:water volume ratio of 20%:80% to 100%:0%) over 4 column volumes to obtain compounds C5 (208 mg) and C6 (112 mg). Fr.2 (62 g) was applied to an 800 g silica gel column using a gradient elution of petroleum ether-ethyl acetate (80%-20%, i.e., from a petroleum ether:ethyl acetate volume ratio of 80%:20% to 20%:80%) over 3 column volumes to yield five fractions (Fr.2a-e). Fr.2b (3 g) was repeatedly subjected to C18 preparative chromatography using a gradient elution of methanol-water (20%-100%, i.e., from a methanol:water volume ratio of 20%:80% to 100%:0%) over 4 column volumes to yield compounds C7 (230 mg) and C8 (183 mg). Fr.3 (80 g) was loaded onto an 800 g silica gel column and gradient eluted with petroleum ether-ethyl acetate (80%-20%, i.e., from a petroleum ether:ethyl acetate volume ratio of 80%:20% to 20%:80%) over a 3 column volume to give four fractions (Fr.3a-d). Fr.2c (2 g) was repeatedly subjected to C18 preparative chromatography using methanol-water (20%-100%, i.e., from a methanol:water volume ratio of 20%:80% to 100%:0%) with a gradient elution volume of 4 column volumes to give compound C3 (106 mg), compound C4 (115 mg), compound C9 (95 mg) and compound C10 (150 mg).Fr.4 (30 g) was placed on a 300 g silica gel column and gradient eluted with petroleum ether-ethyl acetate (70%-10%, i.e., from a petroleum ether:ethyl acetate volume ratio of 70%:30% to 10%:90%) with an elution volume of 3 column volumes to obtain 4 fractions (Fr.4a~d). The fractions were repeatedly subjected to preparative chromatography with methanol-water (20%-100%, i.e., from a methanol:water volume ratio of 20%:80% to 100%:0%) with a gradient elution volume of 4 column volumes to obtain compound C1 (103 mg) and compound C2 (120 mg).

[0298] Each fraction can be analyzed by mass spectrometry (MS), H NMR ( 1 H NMR) and carbon NMR ( 13 C NMR) method can be used to identify the structure, and other known structural analysis methods in the field of organic chemistry can also be combined. Taking compound C3 and compound C8 as examples, the following provides 1 H NMR with 13 C NMR test data.

[0299] Compound C1: 20,24-epoxydammarane (-3β,12β,24R)-12-O-α-L-rhamnopyranosyl-25-hydroxy-3-O-α(-5′-O-acetyl)-L-arabinofuranoside.

[0300] Compound C2: Cyclocarya paliurus glycoside B: (20S,24R)-epoxydammarane-(3β,12β)-25-hydroxyl-12-O-β-D-quinovopyranosyl-3-O-β-D-quinovopyranoside ((20S,24R)-epoxydammarane-(3β,12β)-25-hydroxy-12-O-β-D-rhamnopyranosyl-3-O-β-D-rhamnopyranoside).

[0301] Compound C3: Cyclocarya paliurusin II: (20S)-20-hydroxy-24-OaL-arabinopyranosyl-3,4-secodamm ar-4(28),11,25-trien-3-oic acid ((20S)-20-hydroxy-24-O-α-L-arabinopyranosyl-3,4-didamar-4(28),11,25-trien-3-oic acid), white powder, soluble in organic solvents such as ethanol, methanol, and acetonitrile, Liebermann-Burchard reaction positive, MS m / z: 603.81 [MH] - , 1 1H NMR (DMSO-d6, 400 MHz) and 13C NMR (DMSO-d6, 100 MHz). The structural characterization parameters of compound C3 can be seen in Table 1.

[0302] Compound C4: Cyclocarya paliurus glycoside III: 25-hydroxy-(20S,24R)-epoxy-12R-O-β-o-quinovopyranosyl-3,4-secodammar-4(28)-en,3-oic acid (25-hydroxy-(20S,24R)-epoxy-12R-O-β-pyranosyl-3,4-didamar-4(28)-ene,3-oic acid).

[0303] Compound C5: Cyclocarya paliurus glycoside D: (23E)-(12R,20S)-12,20-dihydroxy-25-methoxy-3,4-secodamm ara-4(28),23-dien-3-oic acid 12-O-β-D-quinovopyranoside ((23E)-(12R,20S)-12,20-dihydroxy-25-methoxy-3,4-didamar-4(28),23-dien-3-oic acid 12-O-β-D-rhamnopyranoside).

[0304] Compound C6: Cyclocarya paliurus glycoside F: (23E)-(12R,20S)-12,20-dihydroxy-25-methoxy-3,4-secodammar a-4(28),23-dien-3-oic acid 12-O-α-Larabinopyranoside ((23E)-(12R,20S)-12,20-dihydroxy-25-methoxy-3,4-didamar-4(28),23-dien-3-oic acid 12-O-α-pyranoarabinoside).

[0305] Compound C7: Cyclocarya paliurus glycoside J: (12R,20S,24S)-20,24-dihydroxy-3,4-secodammara-2(28),25-di en-3-oic acid-12-OaL-arabinopyranoside ((12R,20S,4S)-20,24-dihydroxy-3,4-didamar-2(28),25-diene-3-oic acid 12-O-α-L-arabinopyranoside).

[0306] Compound C8: Cyclocarya paliurusin K: (23E)-(12R,20S)-20-hydroxy-3,4-secodammarane-4(28),23,25-trien-3-oic acid-12-ObD-quinovopyranoside ((23E)-(12R,20S)-20-hydroxy-3,4-didamarane-4(28),23,25-trien-3-oic acid-12-O-β-D-rhamnopyranoside), white powder, soluble in organic solvents such as ethanol, methanol, and acetonitrile, positive in Liebermann-Burchard reaction, MS m / z: 617.55 [MH] - , 1 1H NMR (DMSO-d6, 400 MHz) and 13 C NMR (DMSO-d6, 100 MHz). The structural characterization parameters of compound C8 can be found in Table 1.

[0307] Compound C9: Diecatin A: (23E)-(12R,20S)-12,20,25-trihydroxy-3,4-secodammara-4(28),23-dien-3-oic acid 12-O-β-D-quinovopyranoside ((23E)-(12R,20S)-12,20,25-trihydroxy-3,4-didamar-4(28),23-dien-3-oic acid-12-O-β-D-rhamnopyranoside).

[0308] Compound C10: Diecatin B: (23E)-(12R,20S)-12,20,25-trihydroxy-3,4-secodammara-4(28),23-dien-3-oic acid 12-O-α-L-arabinopyranoside ((23E)-(12R,20S)-12,20,25-trihydroxy-3,4-didamar-4(28),23-dien-3-oic acid-12-O-α-L-arabinopyranoside).

[0309] Table 1. Compound C3 and Compound C8 1 H NMR with 13 C NMR data

[0310] (II) Synthesis and preparation of compound C11

[0311] In an ice-water bath, compound C8 (6 mg, 10 μmol, 1 molar equivalent) and benzyl alcohol (1 mg, 10 μmol) were added to 2 mL of dichloromethane, followed by HOBt (1.8 mg, 13 μmol) and EDC (2.5 mg, 13 μmol). Two to three molar equivalents of DMAP or DIEA were added, depending on the situation. The reaction was allowed to react at room temperature for approximately 10 h, monitored by thin-layer chromatography (TLC). After completion of the reaction, the product was washed three times with 5 mL of 5% hydrochloric acid, three times with 5 mL of 5% sodium bicarbonate, three times with 10 mL of water, and three times with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane / methanol mixed solvent, volume ratio of 100:1 to 10:1) to obtain 6.5 mg of the product (compound C11) in a 93.5% yield.

[0312] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0313] MS m / z:695.4441[M+H] + .

[0314] 1 H-NMR (400MHz, DMSO-d6) δ: 7.33(m,5H),6.13(d,1H),5.74(dt,1H),5.21(s,2H),4.88(s,2H),4.82(s,1H) ,4.65(s,1H),4.36(d,1H),4.12(dt,1H),3.91(dd,2H),3.71(s,1H),3.60(m,1H),3.26(m,2H),3.17(m,1H) ,2.58(td,1H),2.20(m,1H),2.11(m,2H),2.33(dd,1H),1.98(dd,1H),1.80(s,3H),1.78(d,1H),1.71(s,3H ),1.61(m,2H),1.49(m,2H),1.27(m,2H),1.14(s,3H),1.10(m,2H),1.05(s,3H),0.98(s,3H),0.96(s,3H).

[0315] 13C-NMR (100MHz, DMSO-d6) δ: 176.65, 148.25, 142.09, 136.11, 134.83, 128.93, 128.1 9,127.63,127.12,115.05,113.68,100.21,74.87,73.88,73.26,71.39,68.61,66. 84,66.44,51.19,50.51,49.49,49.04,44.56,43.98,40.52,36.86,34.73,32.84,30.92,29.69,27.14,25.99,24.93,24.14,20.20,19.04,18.36,16.69,16.65,15.68.

[0316] (III) Synthesis and preparation of compound C12

[0317] In an ice-water bath, compound C8 (6 mg, 10 μmol, 1 molar equivalent) and methanol (0.3 mg, 10 μmol) were added to 2 mL of dichloromethane, followed by HOBt (1.8 mg, 13 μmol) and EDC (2.5 mg, 13 μmol). Two to three molar equivalents of DMAP or DIEA were added, depending on the situation. The reaction was allowed to react at room temperature for approximately 10 hours, monitored by TLC. After completion of the reaction, the product was washed three times with 5 mL of 5% hydrochloric acid, three times with 5 mL of 5% sodium bicarbonate, three times with 10 mL of water, and three times with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane / methanol mixed solvent, volume ratio of 100:1 to 10:1) to obtain 6.0 mg of the product (compound C12) in a 94.8% yield.

[0318] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0319] MS m / z:633.4291[M+H] + .

[0320] 1H-NMR (400MHz, DMSO-d6) δ: 6.13(d,1H),5.74(dt,1H),5.21(s,2H),4.88(s,2H),4.82(s,1H),4.65(s,1H) ,4.36(d,1H),4.12(dt,1H),3.91(dd,2H),3.71(s,1H),3.64(s,3H),3.60(m,1H),3.26(m,2H),3.17(m,1H) ,2.58(td,1H),2.20(m,1H),2.11(m,2H),2.33(dd,1H),1.98(dd,1H),1.80(s,3H),1.78(d,1H),1.71(s,3H ),1.61(m,2H),1.49(m,2H),1.27(m,2H),1.14(s,3H),1.10(m,2H),1.05(s,3H),0.98(s,3H),0.96(s,3H).

[0321] 13 C-NMR (100MHz, DMSO-d6) δ: 176.65, 148.25, 142.09, 134.83, 128.93, 115.05 ,113.68,100.21,74.87,73.88,73.26,71.39,68.61,66.84,66.44,51.91,51 .19,50.51,49.49,49.04,44.56,43.98,40.52,36.86,34.73,32.84,30.92,29.69,27.14,25.99,24.93,24.14,20.20,19.04,18.36,16.69,16.65,15.68.

[0322] (IV) Synthesis and preparation of compound C13

[0323] In an ice-water bath, compound C8 (6 mg, 10 μmol, 1 molar equivalent) and ethanol (0.45 mg, 10 μmol) were added to 2 mL of dichloromethane, followed by HOBt (1.8 mg, 13 μmol) and EDC (2.5 mg, 13 μmol). Two to three molar equivalents of DMAP or DIEA were added, depending on the situation. The reaction was allowed to react at room temperature for approximately 10 h, monitored by TLC. After completion of the reaction, the product was washed three times with 5 mL of 5% hydrochloric acid, three times with 5 mL of 5% sodium bicarbonate, three times with 10 mL of water, and three times with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane / methanol mixed solvent, volume ratio of 100:1 to 10:1) to obtain 6.1 mg of the product (compound C13) in a 94.3% yield.

[0324] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0325] MS m / z:647.4448[M+H] + .

[0326] 1 H-NMR (400MHz, DMSO-d6) δ: 6.13(d,1H),5.74(dt,1H),5.21(s,2H),4.88(s,2H),4.82(s,1H ),4.65(s,1H),4.36(d,1H),4.12(dt,1H),4.02(q,2H),3.91(dd,2H),3.71(s,1H),3.60(m,1 H),3.26(m,2H),3.17(m,1H),2.58(td,1H),2.20(m,1H),2.11(m,2H),2.33(dd,1H),1.98(dd ,1H),1.80(s,3H),1.78(d,1H),1.71(s,3H),1.61(m,2H),1.49(m,2H),1.27(m,2H),1.14(s, 3H),1.10(m,2H),1.08(t,3H),1.05(s,3H),0.98(s,3H),0.96(s,3H).

[0327] 13 C-NMR (100MHz, DMSO-d6) δ: 176.65,148.25,142.09,134.83,128.93,115.05,1 13.68,100.21,74.87,73.88,73.26,71.39,68.61,66.84,66.44,61.34,51.19 ,50.51,49.49,49.04,44.56,43.98,40.52,36.86,34.73,32.84,30.92,29.69,27.14,25.99,24.93,24.14,20.20,19.04,18.36,16.69,16.65,15.68,14.18.

[0328] (V) Synthesis and preparation of compound C14

[0329] Compound C8 (6 mg, 10 μmol) and isopentene (0.70 mg, 10 μmol) were added to 1 mL of dichloromethane and dissolved. Then, 10 μL of 1.0 M dimethylaluminum chloride (10 μmol) was slowly added dropwise to the reaction mixture at 0°C. The mixture was allowed to react for approximately 10 hours at 0°C, after which it was quenched with water. After completion of the reaction, the mixture was extracted three times with 3 mL of ether, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and purified by column chromatography (mixed solvent of n-hexane / ethyl acetate, 50:1 to 10:1 by volume) to yield 5.2 mg of the product (compound C14) in a 75.4% yield.

[0330] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0331] MS m / z:689.4917[M+H] + .

[0332] 1 H-NMR (400MHz, DMSO-d6) δ: 5.37(d,1H),5.21(s,2H),4.82(s,1H),4.65(s,1H),4.36(d,1H),4.12(dt,1H),3.91( dd,2H),3.71(s,1H),3.60(m,1H),3.26(m,2H),3.17(m,1H),2.58(td,1H),2.20(m,1H),2.11(m,2H),2.33(dd,1H ),2.02(d,2H),1.98(dd,1H),1.78(d,1H),1.71(s,3H),1.67(d,2H),1.65(s,3H),1.61(m,2H),1.49(m,2H),1.45 (q,1H),1.41(m,1H),1.27(m,2H),1.14(s,3H),1.10(m,2H),1.05(s,3H),0.98(s,3H),0.96(s,3H),0.83(d,6H).

[0333] 13C-NMR (100MHz, DMSO-d6) δ: 176.65,148.25,131.12,124.26,100.21,74.87,73.8 8,73.26,71.39,68.61,66.84,66.44,51.19,50.51,49.49,49.04,44.56,43.98,4 0.52,37.31,36.86,36.63,35.47,34.73,32.84,32.75,30.92,29.69,27.14,26.43,25.99,24.93,24.14,22.69,21.11,21.11,20.20,18.36,16.69,16.65,15.68.

[0334] (VI) Synthesis and preparation of compound C15

[0335] Compound C8 (6 mg, 10 μmol) and vinyl methyl ketone (0.70 mg, 10 μmol) were added to 1 mL of dichloromethane and dissolved. Then, 10 μL of dimethylaluminum chloride (1.0 M, 10 μmol) was slowly added dropwise to the reaction mixture at 0°C. The mixture was allowed to react for approximately 10 hours at 0°C, after which it was quenched with water. After completion of the reaction, the mixture was extracted three times with 3 mL of ether, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and purified by column chromatography (mixed solvent of n-hexane / ethyl acetate, 50:1 to 10:1 by volume) to obtain 5.3 mg of the product (compound C15) in a 76.8% yield.

[0336] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0337] MS m / z:689.4552[M+H] + .

[0338] 1H-NMR (400MHz, DMSO-d6) δ: 5.37(d,1H),5.21(s,2H),4.82(s,1H),4.65(s,1H),4.36(d,1H),4.12(dt,1H),3. 91(dd,2H),3.71(s,1H),3.60(m,1H),3.26(m,2H),3.17(m,1H),2.58(td,1H),2.20(m,1H),2.11(m,2H),2.33 (dd,1H),2.22(d,2H),1.98(dd,1H),1.96(s,3H),1.95(d,2H),1.78(d,1H),1.71(s,3H),1.65(s,3H),1.61(m ,2H),1.49(m,2H),1.45(t,1H),1.27(m,2H),1.14(s,3H),1.10(m,2H),1.05(s,3H),0.98(s,3H),0.96(s,3H).

[0339] 13 C-NMR (100MHz, DMSO-d6) δ: 209.51,176.65,148.25,133.12,124.26,100.21,74 .87,73.88,73.26,71.39,68.61,66.84,66.44,51.19,50.51,49.49,49.43,49. 04,44.56,43.98,40.52,36.86,34.73,34.84,32.84,32.55,30.92,30.72,29.69,27.14,25.99,25.63,24.93,24.14,22.67,20.20,18.36,16.69,16.65,15.68.

[0340] (VII) Synthesis and preparation of compound C16

[0341] Trifluoroacetic anhydride (1.09 mL of a 0.5 M solution in dichloromethane, 0.545 mmol) was added dropwise to a solution of C1 (0.519 mmol) and pyridine (0.419 mL, 5.18 mmol) in anhydrous dichloromethane (3.46 mL) at -78°C. The bath was slowly warmed to 0°C over 90 minutes, and the reaction was stirred at 0°C for an additional 20 minutes. The reaction was then quenched with 1N aqueous HCl. The reaction was diluted with n-hexane, stirred vigorously, and warmed to room temperature. The aqueous phase was extracted three times with n-hexane, and the organic layer was washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (n-hexane / ethyl acetate mixed solvent, 100:1 to 10:1 by volume) to obtain 29 mg of the product (compound C16) in a 64.4% yield.

[0342] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0343] MS m / z:892.4798[M+H] + .

[0344] 1 H-NMR (400MHz, DMSO-d6) δ: 4.37(s,1H), 4.51(s,1H), 4.77(s,1H), 4.88(s,1H), 4.51(s,1H), 5.55(d,1H), 4.99(m,1H), 4.14(m, 1H), 4.15(m,1H), 4.51(t,1H), 1.41(m,1H), 1.24(t,1H), 1.85(m,2H), 1.92(m,2H), 1.90(t,2H), 1.50(t,2H), 5.40(d,1H), 3.70 (m,1H), 3.14(m,1H), 3.04(t,1H), 3.90(t,1H), 3.60(t,1H), 3.70(m,1H), 0.94(t,1H), 0.94(t,1H), 1.64(t,2H), 1.70(m,2H), 1 .56(t,2H), 1.56(t,2H), 1.62(m,2H), 4.32(t,2H), 1.20(s,3H), 0.89(s,3H), 0.89(s,3H), 2.04(s,3H), 1.64(s,3H), 1.64(s,3H)

[0345] 13C-NMR (100MHz, DMSO-d6) δ: 113.1,91.2,86.1,85.2,80.0,80.1,50.0,51.9 ,41.1,32.4,26.7,26.8,31.9,109.8,74.2,79.1,92.5,74.1,73.7,72.4,4 0.7,38.1,52.7,55.6,39.1,36.3,25.5,35.2,38.7,18.5,114.6,155.7,170.2,82.8,62.5,26.9,18.5,17.0,18.8,16.1,23.7,23.7,20.7,22.7,22.7.

[0346] (VIII) Synthesis and Preparation of Compound C17

[0347] Trifluoroacetic anhydride (1.09 mL of a 0.5 M solution in dichloromethane, 0.545 mmol) was added dropwise to a solution of C2 (0.519 mmol) and pyridine (0.419 mL, 5.18 mmol) in anhydrous dichloromethane (3.46 mL) at -78°C. The bath was slowly warmed to 0°C over 90 minutes, and the reaction was stirred at 0°C for an additional 20 minutes. The reaction was then quenched with 1N aqueous HCl. The reaction was diluted with n-hexane, stirred vigorously, and warmed to room temperature. The aqueous phase was extracted three times with n-hexane, and the organic layer was washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (n-hexane / ethyl acetate mixed solvent, 100:1 to 10:1 by volume) to obtain 25 mg of the product (compound C17) in a 58.1% yield.

[0348] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0349] MS m / z:864.4849[M+H] + .

[0350] 1 H-NMR (400 MHz, DMSO-d6) δ:

[0351] 4.77(s,1H), 4.77(s,1H), 4.88(s,1H), 4.88(s,1H), 4.51(s,1H), 4.51(s,1H), 4.14(t,1H), 1.41(m,1H), 1.24(t,1H), 1.85(t,2H), 1.92( m,2H), 1.90(m,2H), 1.50(t,2H), 5.40(d,1H), 5.40(d,1H), 3.70(d,1H), 3.70(t,1H), 3.14(m,1H), 3.04(t,1H), 3.90(t,1H), 3.90(t,1H), 3.60(t,1H),3.60(t,1H),3.70(d,1H),,3.70(t,1H),0.94(t,1H),0.94(t,1H),1.64(3,2H),1.70(m,2H),1.56(t,2H),1.56(t,2H),1.62 (m,2H),1.20(s,3H),0.89(s,3H),0.89(s,3H),0.89(s,3H),0.89(s,3H),0.84(s,3H),1.11(s,3H),1.11(s,3H),1.64(s,3H),1.64(s,3H)

[0352] 13 C-NMR (100 MHz, DMSO-d6) δ:

[0353] 91.2,85.2,50.0,51.9,41.1,32.4,26.7,25.8,31.9,109.8,113.7,74.2,74.2,79.1,92.5,74.1,74.1,73.7,73.7,72.4,72.4,40.7,38.1,52.7,55.6,39.1,36.3,25.5,35.2,38.7,18.5,114.6,155.7,82.8,26.9,18.5,17.0,17.0,18.8,16.1,23.7,23.7,22.7,22.7.

[0354] (IX) Synthesis and preparation of compound C18

[0355] In an ice-water bath, compound C3 (6 mg, 10 μmol, 1 molar equivalent) and benzyl alcohol (1 mg, 10 μmol) were added to 2 mL of dichloromethane, followed by HOBt (1.8 mg, 13 μmol) and EDC (2.5 mg, 13 μmol). Two to three molar equivalents of DMAP or DIEA were added, depending on the situation. The reaction was allowed to react at room temperature for approximately 10 hours, monitored by thin-layer chromatography (TLC). After completion of the reaction, the product was washed three times with 5 mL of 5% hydrochloric acid, three times with 5 mL of 5% sodium bicarbonate, three times with 10 mL of water, and three times with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane / methanol mixed solvent, volume ratio of 100:1 to 10:1) to obtain 6.2 mg of the product (compound C18) in an 89.8% yield.

[0356] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0357] MS m / z:694.4448[M+H] + .

[0358] 1 H-NMR (400MHz, DMSO-d6) δ: 4.77(s,1H), 4.74(s,1H), 4.51(s,1H), 4.49(s,1H), 1.34(t,1H), 1.50(t,2H), 1.90(m,2H), 5.40(d,1H), 3 .88(d,2H), 3.90(t,1H), 3.70(m,1H), 3.70(m,1H), 5.90(t,1H), 5.90(t,1H), 7.33(s,1H), 7.33(s,1H), 7.33(s,1H), 7.33(s,1H), 7.33 (s,1H),7.32(s,1H),1.72(d,1H),1.92(t,1H),1.56(t,2H),1.49(m,2H),5.20(d,2H),3.88(d,H),0.89(s,3H),0.89(s,3H),2.35(d, 2H),1.34(t,2H),1.44(m,2H),1.20(s,3H),1.79(s,3H),1.79(s,3H),1.89(3,1H),5.03(s,1H),4.83(s,1H),5.32(s,1H),5.18(s,1H)

[0359] 13C-NMR (100MHz, DMSO-d6) δ: 51.0, 40.7, 50.4, 34.1, 33.1, 107.9, 66.5, 73 .9,70.5,77.2,128.3,40.2,136.1,135.8,127.1,127.1,128.9,128.9,12 7.6,44.5,40.9,51.9,38.4,25.4,173.1,75.9,66.4,87.1,23.9,147.7,2 8.3,18.9,21.5,145.5,113.6,111.6,30.0,45.2,25.7,25.8,22.0,17.7.

[0360] (10) Synthesis and preparation of compound C19

[0361] In an ice-water bath, compound C3 (6 mg, 10 μmol, 1 molar equivalent) and methanol (0.3 mg, 10 μmol) were added to 2 mL of dichloromethane, followed by HOBt (1.8 mg, 13 μmol) and EDC (2.5 mg, 13 μmol). Two to three molar equivalents of DMAP or DIEA were added, depending on the situation. The reaction was allowed to react at room temperature for approximately 10 h, monitored by thin-layer chromatography (TLC). After completion of the reaction, the product was washed three times with 5 mL of 5% hydrochloric acid, three times with 5 mL of 5% sodium bicarbonate, three times with 10 mL of water, and three times with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (dichloromethane / methanol mixed solvent, volume ratio of 100:1 to 10:1) to obtain 5.6 mg of the product (compound C19) in a 90.3% yield.

[0362] 1 H-NMR, 13 C-NMR, MS [M+H] + Characterization results:

[0363] MS m / z:618.4133[M+H] + .

[0364] 1H-NMR (400MHz, DMSO-d6) δ: 4.77(s,1H), 4.74(s,1H), 4.51(s,1H), 4.49(s,1H), 1.34(t,1H), 1.50(t,2H), 1.90(m,2H), 5.40(d,1H),3.88(d,2H),3.90(t,1H),3.70(m,1H),3.70(m,1H),5.90(t,1H),5.90(t,1H),1.72(d,1H),1.92(t,1H),1 .56(t,2H),1.49(m,2H),3.88(d,H),3.61(d,1H),0.89(,3H),1.54(,2H)0.89(,3H),0.89(,3H),2.35(d,2H),1.34(t,2 H),1.44(m,2H),1.20(s,3H),1.79(s,3H),1.79(s,3H),1.89(3,1H),5.03(s,1H),4.83(s,1H),5.32(s,1H),5.18(s,1H)

[0365] 13 C-NMR (100MHz, DMSO-d6) δ: 51.0, 40.7, 50.4, 34.1, 33.1, 107.9, 66.5, 73.9, 70.5, 77.2, 128.3, 40.2, 135.8, 44.5, 40.9, 51.9 ,38.4,25.4,173.1,75.9,87.1,51.9,23.9,147.7,28.3,18.9,21.5,145.5,113.6,111.6,32.9,45.2,25.7,25.8,22.0,17.7.

[0366] Test on the killing effect of diterpenoid and triterpenoid derivatives on bacteria

[0367] (1) Strains and drugs

[0368] Strains: Vancomycin-resistant enterococci (VRE), linezolid-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium abscessus, Helicobacter pylori, and Klebsiella pneumoniae were isolated from the West China Hospital of Sichuan University and provided by the Clinical Microbiology Laboratory: MRSA-1 (clinical number: 1911101191), MRSA-2 (clinical number: 1911081137), MRSA-3 (clinical number: 1911051296), MRSA-4 (clinical number: 1911051125), MRSA-5 (clinical number: 1911081165), VRE (clinical number: 2210251065), linezolid-resistant Enterococci (2207221285), Klebsiella pneumoniae (2208181356), and Helicobacter pylori (2206222518). Staphylococcus aureus (ATCC 25923), Escherichia coli ATCC 25922, Staphylococcus epidermidis ATCC 8099, Staphylococcus saprophyticus, Streptococcus pneumoniae ATCC 6303, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Lactobacillus acidophilus ATCC 4356, Enterococcus faecalis ATCC BAA-1240, Mycobacterium abscessus, and Pseudomonas aeruginosa PA14 were all purchased.

[0369] Drugs: triterpene derivatives (compounds C1 to C15) prepared above, penicillin sodium, oxacillin sodium and vancomycin hydrochloride (commercially available products).

[0370] (2) Bacterial culture

[0371] Culture media: Mueller-Hinton Broth (MHB) was used for Staphylococcus aureus (ATCC 25923), MRSA-1, MRSA-2, MRSA-3, MRSA-4, MRSA-5, Staphylococcus epidermidis, Staphylococcus saprophyticus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Streptococcus pneumoniae, alpha-hemolytic Streptococci, and beta-hemolytic Streptococci were cultured in MHB medium supplemented with 5% serum. Lactobacillus acidophilus ATCC 4356 was cultured in MRS medium. Enterococci faecalis, vancomycin-resistant Enterococci, and linezolid-resistant Enterococci were cultured in trypticase soy broth supplemented with 0.6% yeast extract. Culture conditions: 37°C, shaking at 150 rpm. Helicobacter pylori was cultured in H. pylori medium at 37°C in an incubator with 5% O2 and 5% CO2. Mycobacterium abscessus was cultured in Roche's basal medium at 30°C.

[0372] (III) Bactericidal effect test of triterpenoid derivatives

[0373] Preparation of test bacteria: Inoculate each bacterium into 5 mL of the corresponding culture medium, culture overnight at 37°C in a shaking incubator, adjust the turbidity of the bacterial solution to 0.5 McFarland units, and then dilute the bacterial solution 100 times for later use. The final bacterial concentration is 5×10 5 cfu / mL.

[0374] Preparation of triterpene derivative mother solution: Accurately weigh 7.5 mg of triterpene derivative powder and dissolve it in 1 mL of DMSO to obtain a 7.5 mg / mL triterpene derivative mother solution.

[0375] Preparation of a triterpene derivative drug concentration gradient: Dilute the drug stock solution with the corresponding culture medium to an initial triterpene derivative concentration of 300 μg / mL. Add 100 μL of this drug solution to wells 1 and 2 of a 96-well plate. From well 2 onward, add 100 μL of culture medium to perform serial dilutions up to well 9. Set well 10 as the culture medium control. From wells 1 to 9, the concentrations of the triterpene derivative are 150 μg / mL, 75 μg / mL, 37.5 μg / mL, 18.75 μg / mL, 9.375 μg / mL, 4.6875 μg / mL, 2.34375 μg / mL, 1.171875 μg / mL, and 0.5859375 μg / mL, respectively.

[0376] To test for antibacterial activity, add 100 μL of the bacterial solution prepared above to the wells containing each triterpene derivative concentration and the culture medium control wells. After thorough mixing, incubate overnight at 37°C in a humidified chamber. The lowest drug concentration resulting in no bacterial growth is determined as the minimum inhibitory concentration (MIC).

[0377] If “no colony growth” could not be achieved at any of the above concentrations, the MIC was recorded as “>150 μg / mL”.

[0378] MIC can be used to characterize antibacterial activity. The lower the MIC value, the lower the effective antibacterial concentration and the stronger the antibacterial efficacy.

[0379] The test results can be found in Table 2-3.

[0380] (4) Test results

[0381] As can be seen from Tables 2 to 4, these triterpene derivatives not only have a killing effect on the standard strain of common Staphylococcus aureus (ATCC25923), but also have a significant killing effect on various MRSA strains. In addition, triterpene derivatives also have a good killing effect on Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic Streptococcus, and beta-hemolytic Streptococcus. Some triterpene derivatives also have a good killing effect on Escherichia coli, Enterococcus faecalis, vancomycin-resistant Enterococcus, linezolid-resistant Enterococcus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori, and Mycobacterium abscessus. At the same time, each triterpene derivative shows certain selectivity to different strains, for example, the MIC for Lactobacillus acidophilus is higher. When the drug containing these triterpene derivatives is delivered in an oral manner, the impact on the normal flora of the gastrointestinal tract is limited.

[0382] Furthermore, Tables 2 through 4 show that while C0 and C4-C15 share similar core structures, different R1, R4, and R8 components enable some compounds to achieve enhanced killing effects against key bacterial strains. For example, at the highest concentration tested, C0 had no inhibitory effect against vancomycin-resistant Enterococci, linezolid-resistant Enterococci, and Klebsiella pneumoniae. However, among C4-C15 compounds, C5 exhibited significantly enhanced inhibitory effects against these bacteria compared to C0.

[0383] Table 2. MIC test values ​​of triterpenoid derivatives against various bacteria (μg / mL)

[0384] Table 3. MIC test values ​​of triterpenoid derivatives against various bacteria (μg / mL)

[0385] Table 4. MIC test values ​​of triterpenoid derivatives against various bacteria (μg / mL)

[0386] The chemical formula of C0 in Table 4 is:

[0387] Analysis of the antibacterial mechanism of diterpenoid and triterpenoid derivatives

[0388] Analysis method: The two-dimensional molecular formula of the triterpene derivative of formula (I) was drawn in ChemDraw 18.0 software and exported as a .sdf format structure as a ligand. The FtsZ / GTP complex structure was used as a template, and the X-ray crystal structure of the complex was obtained from the PDB database (PDB ID: 5MN5). Molecular docking was performed using Schrödinger The Glide software package was run in its SP mode. Ligand compounds were pretreated using LigPrep with default parameters, and protein complexes were pretreated using Protein Preparation. After docking, the docking results were analyzed using PyMol software.

[0389] The "docking score" of each compound on FtsZ, a representative of Staphylococcus aureus, is used to characterize the binding strength of the compound to FtsZ. A more negative docking score indicates a stronger binding affinity between the compound and FtsZ.

[0390] The test results can be found in Table 4.

[0391] Compound C15 had the most negative docking score, indicating the strongest binding to FtsZ and relatively stronger antibacterial activity against various bacteria, consistent with the test results in Tables 2 and 3. This is likely due to the presence of a carboxyl group in compound C15 and the introduction of an electron-withdrawing ketone carbonyl group into R8, which allows compound C15 to form hydrogen bonds with Gly110 and Asn44 in the GTP-binding domain of FtsZ, resulting in stronger binding between compound C15 and FtsZ.

[0392] For compound C1, the binding force between compound C1 and FtsZ may be weaker due to the larger molecular radius of compound C1, which increases the steric hindrance with the GTP binding domain of FtsZ and weakens the binding strength between the molecule and the binding domain.

[0393] The binding force between compounds C12 and C13 and FtsZ is relatively weak, which may be because R4 is methyl or ethyl, the active hydrogen disappears, and hydrogen bonds cannot be formed.

[0394] Compound C0 showed no inhibitory activity against vancomycin-resistant Enterococci, linezolid-resistant Enterococci, and Klebsiella pneumoniae at the highest concentration tested. This may be due to the fact that compound C0's glycoside is an arabinopyranoside, while compound C8's glycoside is a rhamnopyranoside. Rhamnopyranose, compared to arabinopyranose, is more easily able to cross the bacterial cell membrane and reach the cytoplasm to bind to FtsZ. Furthermore, compound C0's docking score with FtsZ was -4.955, while C8's was -5.593, indicating that compound C0's binding to FtsZ was weaker than C8's. Compounds C11, C14, and C15, derived from C8 through chemical synthesis, increased their binding to FtsZ and enhanced their antibacterial activity. These differences in glycoside binding lead to differences in binding affinity, suggesting differences in antibacterial efficacy.

[0395] Table 4. Molecular docking results (binding strength)

[0396] Furthermore, the amino acid sequence and protein structure of FtsZ differ between different bacteria, potentially leading to varying antibacterial activity against different bacteria. For example, the sequence similarity between Staphylococcus aureus FtsZ and Pseudomonas aeruginosa FtsZ is only 53%. Compound C0 inhibits the growth of S. aureus but has no effect on P. aeruginosa. To address this phenomenon, molecular docking simulations were conducted to investigate the docking scores of compound C0 with P. aeruginosa FtsZ. Data analysis revealed that compound C0 had a docking score of -1.005, indicating poor binding to P. aeruginosa FtsZ. Compound C5 exhibited significant differences in R8 from C0, enabling C5 to inhibit not only the growth of S. aureus but also that of P. aeruginosa. Molecular docking analysis revealed that C5 had a docking score of -2.115 with P. aeruginosa FtsZ, indicating enhanced binding compared to compound C0. Therefore, C5 also exhibited growth inhibition against P. aeruginosa.

[0397] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0398] The above-described embodiments merely represent several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that a person of ordinary skill in the art may make various modifications and improvements without departing from the spirit of the present application, and these modifications and improvements fall within the scope of protection of the present application. Therefore, the scope of protection of the present patent application shall be determined by the appended claims.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, in, is -CH=CH- or -CH2-CHR1-; R1 is selected from any one of a pyranose ring glycoside, a pyranose ring glycoside with one -OH acetylated, a furanose ring glycoside, and a furanose ring glycoside with one -OH acetylated; R2 is -(CH2)2-C(=O)-O-R4 and R3 is -CH(=CH2)-CH3, or R2 and R3 are both -(CR5R6)2- and R2 and R3 form a saturated 6-membered ring with adjacent carbon atoms; Any R5 and any R6 are independently H, methyl or -OR7; R4 and any one of R7 are independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocycloalkyl and substituted or unsubstituted phenyl C 1-6 Alkyl; among which, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 is selected from O and N, C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is one or more; Substituted C 1-6 Alkyl, substituted C 3-6 Cycloalkyl, substituted C 3-6 Heterocycloalkyl and substituted phenyl C 1-6 In the alkyl group, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and phenyl C 1-6 The H in the alkyl group is independently substituted by one or more Q1, and any Q1 is independently selected from -F, -Cl, -Br, -NH2, -NO2, acetyl, CH3C(=O)-O-CH2-, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted-[O-divalent C 5-6 Heterocycloalkyl] n -OH; Substituted-[O-divalent C 5-6 Heterocycloalkyl] n -OH, divalent C 5-6 The H in the heterocycloalkyl group is substituted by one or more Q2, any Q2 being independently -CH3 or -OH, -CH3 and -OH being in the divalent C 5-6 The number of all Q2 in the heterocycloalkyl group is independently 1 to 4, and the divalent C 5-6 The ring atoms in the heterocycloalkyl group include heteroatoms X2, wherein the heteroatoms X2 are selected from O and N, divalent C 5-6 The number of the heteroatom X2 in the heterocycloalkyl group is one or more, and n is 0, 1, 2, 3, 4 or 5; R8 is selected from: Where R a and R b are independently selected from H, -OH, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-O-, substituted or unsubstituted C 3-6 Cycloalkyl-O- and substituted or unsubstituted C 3-6 Heterocycloalkyl-O-, wherein the substituted C 1-6 Alkyl, substituted C 1-6 Alkyl-O-, substituted C 3-6 Cycloalkyl-O- and substituted C 3-6 Heterocycloalkyl-O-, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O- and C 3-6 The H in heterocycloalkyl-O- is independently substituted by one or more Q3, any Q3 being independently selected from: -OH, methyl, ethyl, acetyl, methoxy, ethoxy, -F, -Cl and -Br; C 3-6 The ring atoms in the heterocycloalkyl group include a heteroatom X3, wherein the heteroatom X3 is selected from O and N; R c Any one independently selected from trifluoroacetyl, trichloroacetyl and tribromoacetyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (II) or a compound of formula (III):

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R1 is selected from and any of the foregoing groups wherein one -OH group is acetylated.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R4 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl or phenyl C 1-6 Alkyl; among which, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 is selected from O and N, C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is one or two; Any R7 is independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocycloalkyl and substituted or unsubstituted phenyl C 1-6 Alkyl; among which, C 3-6 The ring atoms in the heterocycloalkyl group include heteroatoms X1, wherein the heteroatoms X1 is selected from O and N, C 3-6 The number of the heteroatom X1 in the heterocycloalkyl group is one or more; Among them, the substituted C 1-6 Alkyl, substituted C 3-6 Cycloalkyl, substituted C 3-6 Heterocycloalkyl and substituted phenyl C 1-6 In the alkyl group, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and phenyl C 1-6 The H in the alkyl group is independently substituted by one or more Q1, wherein any one of Q1 is independently selected from -OH, -F, -Cl, -Br, -NH2, -NO2, acetyl, CH3C(=O)-O-CH2-, C 1-6 Alkyl, C 1-6 Alkyl-O-, C 3-6 Cycloalkyl-O-, and substituted or unsubstituted-[OZ] n -OH, Wherein, -OZ- is a divalent pyranose ring group or a divalent furanose ring group, Z contains -OH, and n is 1, 2, 3, 4 or 5. When n is greater than 1, adjacent -OZ- are connected by glycosidic bonds.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: Any C 1-6 Alkyl is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; Any C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Any C 3-6 Heterocycloalkyl is independently oxirane, tetrahydropyranyl or tetrahydrofuranyl; Any bivalent C 5-6 The heterocycloalkyl group is independently a divalent tetrahydropyranyl group or a divalent tetrahydrofuranyl group.

6. The compound according to claim 5 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: Substituted or unsubstituted C 3-6 Heterocycloalkyl is Or the aforementioned group in which one -OH is acetylated.

7. The compound according to claim 5 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: Substituted or unsubstituted C 3-6 Heterocycloalkyl is 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (Ia), a compound of formula (Ib) or a compound of formula (Ic); 9. The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (Ib) or a compound of formula (Ic), R4 is H, C 1-3 Alkyl or benzyl.

10. The compound according to claim 9 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R4 is H.

11. The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (Ia) or (Ic), and R1 is a pyranose ring type glycosyl group or a furanose ring type glycosyl group.

12. The compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R1 is arabinopyranosyl or rhamnopyranosyl.

13. The compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R1 is 14. The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: In R8, R a and R b are independently H, -OH, C 1-3 Alkyl-O-, pyranose ring type glycosyl or furanose ring type glycosyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: In R8, R a and R b are each independently H, -OH, methoxy or α-L-arabinopyranosyl.

16. The compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (Ic); In R8, R a and R b are each independently H, -OH or methoxy.

17. The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R7 is H, arabinopyranosyl, arabinopyranosyl with one hydroxyl group acetylated, arabinofuranosyl, arabinofuranosyl with one hydroxyl group acetylated, rhamnopyranosyl, or rhamnopyranosyl with one hydroxyl group acetylated.

18. The compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R7 is 19. The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: (Ia) In the compound, R1 is R7 is R8 is Among them, R c Independently selected from any one of trifluoroacetyl, trichloroacetyl and tribromoacetyl; (Ib) In the compound, R4 is H, methyl, ethyl or benzyl, and R8 is R a for (Ic) In the compound, R1 is R4 is H, methyl, ethyl or benzyl, R8 is 20. The compound according to any one of claims 8, 14 to 19, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is compound (Ic), R1 is arabinopyranosyl or rhamnopyranosyl, R4 is H or benzyl, and R8 is 21. The compound according to claim 20 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R1 is 22. The compound according to any one of claims 8, 14 to 19, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (Ic); the compound of formula (Ic) satisfies one, two or three of the following characteristics: R1 is a pyranose ring or furanose ring; R8 is R4 is H or benzyl.

23. The compound according to claim 22 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R1 is arabinopyranosyl or rhamnopyranosyl; R8 is R4 is H or benzyl.

24. The compound according to any one of claims 8, 14 to 19, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The compound represented by formula (I) is a compound of formula (Ic); the compound of formula (Ic) satisfies one, two or three of the following characteristics: R1 is a pyranose ring or furanose ring; R8 is R4 is H or benzyl.

25. The compound according to claim 24 or a pharmaceutically acceptable salt or solvate thereof, characterized in that R1 is arabinopyranosyl or rhamnopyranosyl; R8 is R4 is H or benzyl.

26. The compound according to claim 24 or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R8 is R4 is H.

27. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that The compound represented by formula (I) is any of the following compounds:

28. An antibacterial composition, characterized in that The invention comprises a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof.

29. Use of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof in the preparation of an antibacterial composition.

30. The use according to claim 29, characterized in that The compound represented by formula (I) or its pharmaceutically acceptable salt or solvate is used in any suitable form of any of the following groups: Group A: tablets, capsules, granules, pills, ointments, solutions, suspensions, emulsions and creams; Group B: oral solutions, lozenges, injections, suppositories, sprays, drops, patches, and tube feeding preparations; Group C: Surface coatings of solid articles and inclusions in solid articles, wherein the solid articles include at least plastic articles.

31. An antibacterial drug comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

32. A method for treating, ameliorating or preventing bacterial infection, comprising administering an effective amount of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.

33. The method according to claim 32, characterized in that The bacteria are one or more of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, linezolid-resistant enterococci, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic streptococci, beta-hemolytic streptococci, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

34. The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof, for use in treating, ameliorating or preventing bacterial infection or a disease caused by bacterial infection.

35. The compound according to claim 34 or a pharmaceutically acceptable salt or solvate thereof, characterized in that The bacteria are one or more of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, linezolid-resistant enterococci, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, alpha-hemolytic streptococci, beta-hemolytic streptococci, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus, and the diseases caused by the bacterial infection include diseases caused by drug-resistant bacterial infection. Optionally, the drug-resistant bacterial infection diseases include diseases caused by infection with at least one of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and linezolid-resistant enterococci.

36. A product comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof.

37. A method for using the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof as an antibacterial active substance, comprising adding the compound or a pharmaceutically acceptable salt or solvate thereof to a desired product or coating the surface of the product.

38. The product of claim 36 or the method of claim 37, wherein: The product includes at least one of medical devices, daily necessities, cosmetics and packaging supplies, and the daily necessities include one or more of cleaning supplies, sanitary care supplies, bedding, kitchen utensils, dining utensils and toys.

39. A disinfectant comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof.

40. A method for disinfection, comprising applying the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof to a target in need thereof.

41. Use of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof as a disinfectant.

42. An inhibitor of FtsZ protein, comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof.

43. A method for inhibiting FtsZ protein, comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof.

44. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof as an inhibitor of FtsZ protein.

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