WO2025060336A1 - Triterpene derivative or pharmaceutically acceptable salt or solvate thereof, and antibacterial use thereof - Google Patents

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

Related Applications

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

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

Background Art

With the widespread use of antibiotics, especially the abuse of antibiotics, bacterial resistance to commonly used antibiotics has continued to increase, and the emergence of resistant bacteria has reduced the efficacy of antibiotics. This has led to new challenges in the treatment of bacterial infections, and some resistant bacterial infections cannot even find effective treatments. For example, for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), the current antibiotic treatment effects are not ideal.

Summary of the invention

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

in, is -CH=CH- or -CH ₂ -CHR ₁ -;

_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 is acetylated;

R ₂ is -(CH ₂ ) ₂ -C(=O)-OR ₄ and R ₃ is -CH(=CH ₂ )-CH ₃ , or R ₂ and R ₃ are both -(CR ₅ R ₆ ) ₂ - and R ₂ and R ₃ form a saturated 6-membered ring with adjacent carbon atoms;

Any one of R ₅ and any one of R ₆ are independently H, methyl or -OR ₇ ;

R ₄ and any one of R ₇ 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 the ring atoms in the C _3-6 heterocycloalkyl include heteroatom X ₁ , and the heteroatom X ₁ is selected from O and N, and the number of the heteroatom X ₁ in the C _3-6 heterocycloalkyl is one or more;

In the substituted C _1-6 alkyl, substituted C _3-6 cycloalkyl, substituted C _3-6 heterocycloalkyl and substituted phenyl C _1-6 alkyl, H in the C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl and phenyl C _1-6 alkyl is independently substituted by one or more Q ₁ , any Q ₁ is independently selected from -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl, acetoxymethyl (CH ₃ C(═O)—O—CH ₂ —), 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;

In the substituted -[O-divalent C _5-6 heterocycloalkyl] _n -OH, H in the divalent C _5-6 heterocycloalkyl is replaced by one or more Q ₂ , any Q ₂ is independently -CH ₃ or -OH, the number of -CH ₃ and -OH in all Q ₂ of the divalent C _5-6 heterocycloalkyl is independently 1 to 4, the ring atoms in the divalent C _5-6 heterocycloalkyl include heteroatom X ₂ , the heteroatom X ₂ is selected from O and N, the number of heteroatom X ₂ in the divalent C _5-6 heterocycloalkyl is one or more, and n is 0, 1, 2, 3, 4 or 5;

R ₈ is selected from:

wherein ^Ra and ^Rb are independently selected from H, -OH, substituted or unsubstituted _C1-6 alkyl, substituted or unsubstituted _C1-6 alkyl-O-, substituted or unsubstituted _C3-6 cycloalkyl-O- and substituted or unsubstituted C3-6 heterocycloalkyl-O-, wherein among the substituted _C1-6 alkyl, substituted _C1-6 alkyl-O-, substituted _C3-6 cycloalkyl-O- and substituted _C3-6 heterocycloalkyl-O-, _C1-6 alkyl, _C1-6 alkyl-O-, _C3-6 cycloalkyl-O- and _C3-6 heterocycloalkyl- _O- are independently substituted by one or more _Q3 , any one of _which is independently selected from: -OH, methyl, ethyl, acetyl, methoxy, ethoxy, -F, -Cl and -Br; the ring atoms in the _C3-6 heterocycloalkyl include heteroatom _X3 , and the heteroatom _X3 is selected from O and N; R ^c is independently selected from any one of trifluoroacetyl, trichloroacetyl and tribromoacetyl.

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.

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.

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.

In the fifth aspect of the present application, a method for treating, ameliorating 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.

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.

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.

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.

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.

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 supplies, bedding, kitchen utensils, dining utensils and toys.

In the ninth aspect of the present application, a disinfectant is provided, comprising a compound represented by formula (I) or a pharmaceutically acceptable salts or solvates.

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 a solvate thereof to a target object in need.

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; the use is for non-therapeutic purposes.

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.

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.

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.

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 Enterococcus and linezolid-resistant Enterococcus.

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.

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:

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

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

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.

The applicant of the present application has unexpectedly discovered, after a large number of experimental explorations, that a class of triterpene derivatives has high bactericidal activity against some antibiotic-resistant strains, and in addition, has broad-spectrum antibacterial activity, and has strong killing effects 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, and in addition, has 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.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the technical solutions in the embodiments of the present application or the conventional technology, the drawings required for use in the embodiments or the conventional technology descriptions are briefly introduced below. 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.

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 visualization 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.

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 visualization 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.

FIG3 is a schematic diagram of the binding pocket of FtsZ, wherein the light-colored portion is the binding pocket region.

DETAILED DESCRIPTION

In order to make the above-mentioned purposes, features and advantages of the present application more obvious and understandable, the specific implementation methods of the present application are described in detail below in conjunction with the accompanying drawings. Many specific details are set forth in the following description 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 do so without violating the above-mentioned provisions. Similar improvements are made in the context of 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 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.

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

The terms "and/or", "or/and", and "and/or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, which include any combination of any two related listed items, any more related listed items, or all related listed items. For example, "A and/or B" includes three parallel solutions: A, B, and "a combination of A and B".

In the present application, "plurality", "multiple", "multiple times", "multiple", "several", etc., unless otherwise specified, refer to a quantity greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

In this application, unless otherwise specified, "one or more" means any one of the listed items or any combination of the listed items. Similarly, "one or more" and the like, when used in other ways to mean "one or more", are also understood in the same way unless otherwise specified.

As used herein, "combination thereof", "any combination thereof", "any combination thereof" etc. include all suitable combinations of any two or more of the listed items.

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.

Herein, "preferred", "better", "more preferred", and "suitable" are only used to describe implementation methods or examples with better effects, and it should be understood that they do not constitute a limitation on the scope of protection of this application. If multiple "preferred" items appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "preferred" item is independent.

In this application, "further", "further", "particularly", "for example", "such as", "example", "for example", etc. are used for descriptive purposes, indicating that the previous and subsequent technical solutions are related in terms of the content covered, but should not be understood as a limitation on the previous technical solution, nor can it be understood as a limitation on the protection scope 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 can be understood that A is not limited to B.

In this application, "optionally", "optional", and "optional" mean optional or dispensable, that is, any one of the two parallel schemes of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "option" is independent.

In the present application, the terms "first", "second", "third", "fourth", etc. in "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

The terms "containing", "including" and "comprising" 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 by words such as "containing", "including" and "comprising" 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.

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.

In this application, when it comes to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional values in the numerical interval is considered to be continuous and includes the two numerical endpoints of the numerical interval (i.e., the minimum value and the maximum value), and every numerical value between the two numerical endpoints. Unless otherwise specified, when a numerical interval refers only to integers in the numerical interval, it includes the two endpoint integers of the numerical range, and every integer between the two endpoints, which is equivalent to directly listing Each integer is cited. When multiple numerical ranges are provided to describe a feature or characteristic, these numerical ranges can be combined. In other words, unless otherwise specified, the numerical ranges disclosed herein should be understood to include any and all subranges included therein. The "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.

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 with all contents and all purposes. When the 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 the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of 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 modified adaptively according to the description of this application.

In this application, if there are multiple steps involved in the method flow, unless there is a clear different description in this document, there is no strict order restriction on the execution of these steps, and they can be executed in other orders than described. Moreover, any step can include multiple sub-steps or multiple stages, and these sub-steps or stages are not necessarily executed 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.

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

The temperature parameters in this application, unless otherwise specified, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

In the present 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 the present application, "room temperature" or "normal temperature" refers to 10°C to 30°C. In some embodiments of the present application, "room temperature" or "normal temperature" refers to 20°C to 30°C.

In this application, when referring to the unit of a data range, if there is a unit only after the right endpoint, it means that the units of the left endpoint and the right endpoint 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).

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

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.

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".

Herein, the term "alkyl" refers to a monovalent residue formed by the loss of a 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. A phrase containing the term, for example, "C _1-6 alkyl" refers to an alkyl containing 1 to 6 carbon atoms, and each occurrence may be independently C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl or C ₆ alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH 2 CH _{2 CH 3} ), 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 ( _{-CH2CH2CH2CH2CH3} ), 2-hexyl ( _-CH ( _CH3 ) _CH2CH2CH2CH3 ), 3-hexyl ( _-CH ( _CH2CH3 )(CH2CH2CH3)), 2-methyl- ₂ -pentyl (-C _{( CH3} )2CH2CH2CH3), 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 (-C(CH3 _)2CH2CH2CH3 ), ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (—C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ) and 3,3-dimethyl-2-butyl(—CH(CH ₃ )C(CH ₃ ) ₃ .

Herein, the term "cycloalkyl" refers to a monovalent residue formed by the loss of a hydrogen atom on a ring of a non-aromatic hydrocarbon (which may be a saturated hydrocarbon or an unsaturated hydrocarbon) containing a ring structure, i.e., a monovalent attachment site is formed directly on the ring. Phrases containing this term, for example, "C _3-6 cycloalkyl" refers to a cycloalkyl containing 3 to 6 carbon atoms, and each occurrence may be independently C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl or C ₆ cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl Cyclobutyl Cyclopentyl Cyclohexyl Cyclohexenyl (including but not limited to ).

As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, which refers to a monovalent residue formed by a saturated hydrocarbon containing a ring structure losing a hydrogen atom on the ring, i.e., a monovalent attachment site is formed directly on the ring. Phrases containing this term, for example, "C _3-6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, and each occurrence may be independently C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl or C ₆ cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl Cyclobutyl Cyclopentyl Cyclohexyl

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. A phrase containing this term, for example, " _{C3-6heterocycloalkyl} " refers to a heterocycloalkyl group containing ₃ to 6 carbon atoms, and each occurrence may be independently C3heterocycloalkyl, _{C4heterocycloalkyl} , _{C5heterocycloalkyl} or _{C6heterocycloalkyl} . Suitable examples of ring structures in heterocycloalkyl groups include tetrahydrofuran ring. Tetrahydrofuran ring

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.

As used herein, the term "alkoxy" refers to a group having the structure "alkyl-O-", i.e., an alkyl group as defined above is attached to an adjacent group via an oxygen atom. Phrases containing this term, for example, "C _{1 -6} alkoxy" means that the alkyl portion contains 1-6 carbon atoms, and each occurrence may be independently C ₁ alkoxy, C ₄ alkoxy, C ₅ alkoxy or C ₆ alkoxy. Suitable examples include, but are not limited to, methoxy (-O-CH ₃ or -OMe), ethoxy (-O-CH ₂ CH ₃ or -OEt) and tert-butoxy (-OC(CH ₃ ) ₃ or -OtBu).

Herein, the term "divalent heterocycloalkyl" refers to a divalent residue having two monovalent radical centers derived from a heterocycloalkyl group by losing 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, each occurrence of which can be independently a divalent C ₅ heterocycloalkyl group or a divalent C ₆ heterocycloalkyl group. 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 are wait.

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

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, and in addition, 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 Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, vancomycin-resistant Enterococcus, linezolid-resistant Enterococcus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

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

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 replaced. The H on the ring-forming carbon atom of A ₁ is not substituted and the H on the ring-forming carbon atom of A ₂ is substituted by a substituent; R ₈ is a chemical group having 5 to 20 carbon atoms; R ₂ and R ₃ are monovalent groups, or are connected to each other and adjacent carbon atoms to form a six-membered carbon ring, and the six-membered carbon ring may be substituted or unsubstituted. Among them, the substituent connected to the ring-forming carbon atom in A ₂ can be recorded as R ₁ , R ₁ is a monovalent group, and R ₁ can be a substituted or unsubstituted pyranose ring glycosyl or a substituted or unsubstituted furose ring glycosyl.

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- ).

when When it is a carbon-carbon double bond, _A2 is =CH-; when When it is a carbon-carbon single bond, A ₂ is a methylene group substituted by R ₁ (—CHR ₁ —).

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

In the present application, "solvate" means that a given compound or its salt further includes 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.

In some embodiments, in the triterpene derivative represented by formula (I), It is -CH=CH- or -CH2 _{- CHR1-} , _R1 is a substituted or unsubstituted pyranose ring group or a substituted or unsubstituted furanose ring group, _R8 is a group having 5 to 20 carbon atoms, _R2 and _R3 are respectively monovalent groups, or are connected to each other and adjacent carbon atoms to form a six-membered carbon ring, and the six-membered carbon ring may be substituted or unsubstituted.

In some embodiments, the ring-forming carbon atoms in _A1 and _A2 may each independently be connected only to hydrogen atoms.

In other embodiments, the H on the ring-forming carbon atom in _A1 is not substituted, the ring-forming carbon atom in _A2 is connected to a substituent, and the substituent connected to the ring-forming carbon atom in _A2 can be recorded as _R1 . _R1 can be a substituted or unsubstituted pyranose ring glycosyl or a substituted or unsubstituted furanose ring glycosyl, wherein the H in any hydroxyl group (-OH) in the pyranose ring glycosyl or furanose ring glycosyl can be substituted by an acetyl group, so that the hydroxyl group is acetylated to form _CH3C (=O)O-.

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, such as non-limiting examples. wait.

In some embodiments, It is -CH=CH- or -CH ₂ -CHR ₁ -.

In some embodiments, It is -CH=CH-.

In some embodiments, It is -CH ₂ -CHR ₁ -.

In some embodiments, R ₁ is selected from any one of a pyranose ring group, a pyranose ring group in which one -OH is acetylated, a furanose ring group, and a furanose ring group in which one -OH is acetylated.

In some embodiments, R ₁ is a pyranosyl or furanosyl ring.

In some embodiments, _R1 is arabinofuranosyl, arabinofuranosyl with one -OH acetylated, Any of arabinopyranosyl, arabinopyranosyl in which one -OH group is acetylated, rhamnopyranosyl, and rhamnopyranosyl in which one -OH group is acetylated.

In some embodiments, R ₁ is arabinofuranosyl, arabinopyranosyl, or rhamnopyranosyl.

Non-limiting examples of arabinofuranosyl groups include

Non-limiting examples of arabinopyranosyl groups include

Non-limiting examples of rhamnopyranosyl groups are

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

In some embodiments, R ₁ is

In some embodiments, _R is selected from Any of

In some embodiments, R ₁ is arabinopyranosyl or rhamnopyranosyl.

In some embodiments, R ₁ is any one of α-L-arabinopyranosyl, α-L-rhamnopyranosyl, β-D-rhamnopyranosyl, and any of the foregoing groups in which one -OH is acetylated.

In some embodiments, R ₁ is α-L-arabinopyranosyl, α-L-rhamnopyranosyl, or β-D-rhamnopyranosyl.

In some embodiments, R ₁ is and any of the foregoing groups wherein one -OH group is acetylated.

In some embodiments, R ₁ is

In some embodiments, R ₁ is

In some embodiments, R ₁ is

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

Wherein, ^Ra and ^Rb can be each independently selected from H, hydroxyl (-OH), substituted or unsubstituted alkyl (alkyl can be _C1-6 alkyl), substituted or unsubstituted alkoxy (alkoxy can be _C1-6 alkyl-O-), substituted or unsubstituted cycloalkyloxy (cycloalkyloxy can be _C3-6 cycloalkyl-O-), substituted or unsubstituted heterocycloalkyloxy (heterocycloalkyloxy can be _C3-6 heterocycloalkyl-O-); ^Rc is independently selected from any one of trifluoroacetyl, trichloroacetyl and tribromoacetyl.

In the definition of _R8 , in the substituted alkyl, substituted alkoxy, substituted cycloalkyloxy and substituted heterocycloalkyloxy, the H on the alkyl (e.g. _C1-6 alkyl), alkoxy (e.g. _C1-6 alkyl-O-), cycloalkyloxy (e.g. _C3-6 cycloalkyl-O-) and heterocycloalkyloxy (e.g. _C3-6 heterocycloalkyl-O-) groups are independently substituted by one or more substituents _Q3 , and any _Q3 is independently selected from -OH, _C1-3 alkyl (e.g. methyl, ethyl), _C1-3 alkoxy (i.e. _C1-3 alkyl-O, such as methoxy, ethoxy) and halogen (e.g. fluoro (-F), chloro (-Cl), bromo (-Br)).

In the definition of _R8 , the ring-forming atoms in "heterocycloalkyl (such as _{C3-6heterocycloalkyl} )" include heteroatom _X3 , and the heteroatom _X3 may be selected from O and N, and further may be O. This definition is applicable to independently described heterocycloalkyl (such as _{C3-6heterocycloalkyl} ) and to the corresponding parts in heterocycloalkyloxy (such as heterocycloalkyl-O-, and further such as _{C3-6heterocycloalkyl} -O-).

In the definition of R ₈ , the number of the heteroatom X ₃ in the heterocycloalkyl group (such as C _3-6 heterocycloalkyl group) can be one or more, for example, 1 or 2; in some embodiments, the number of the heteroatom X ₃ in the heterocycloalkyl group (such as C _3-6 heterocycloalkyl group) is 1.

In the present application, unless otherwise specified, "C _1-6 alkyl" appearing anywhere may be independently C _1-5 alkyl, further may be C _1-4 alkyl, and further may be C _1-3 alkyl. "C _1-6 alkyl" appearing anywhere may be independently selected from C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C _{5 alkyl and C 6 alkyl} . "C _1-6 alkyl" appearing anywhere may be independently selected from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. In some embodiments, C _1-6 alkyl may be methyl or ethyl. In some embodiments, C _1-6 alkyl may be methyl.

In the present application, unless otherwise specified, any occurrence of "C _3-6 cycloalkyl" may independently be C _3-5 cycloalkyl, further optionally C _3-4 cycloalkyl, and further optionally C ₃ cycloalkyl _. is independently selected from C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl and C ₆ cycloalkyl. Any occurrence of "C _3-6 cycloalkyl" may be independently selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present application, unless otherwise specified, any occurrence of "C _3-6 heterocycloalkyl" may be independently selected from C _3-5 heterocycloalkyl, further selected from C _3-4 heterocycloalkyl, and further selected from C ₃ heterocycloalkyl. Any occurrence of "C _3-6 heterocycloalkyl" may be independently selected from C ₃ heterocycloalkyl, C ₄ heterocycloalkyl, C ₅ heterocycloalkyl and C ₆ heterocycloalkyl. Any occurrence of "C _3-6 heterocycloalkyl" in the ring structure may be independently selected from: ethylene oxide ring Tetrahydrofuran ring and tetrahydropyran ring The corresponding heterocycloalkyl groups are oxirane, tetrahydrofuranyl and tetrahydropyranyl.

In some embodiments, in R ₈ , ^Ra and ^Rb are each independently H, -OH, C _1-3 alkyl-O-, a pyranosyl group or a furanosyl group.

In some embodiments, in R ₈ , ^Ra and R ^b are each independently H, -OH, methoxy or α-L-arabinopyranosyl.

In some embodiments, in R ₈ , ^Ra and R ^b are each independently H, -OH or methoxy.

In some embodiments, ^Ra is -OH or a pyranose ring group, further can be -OH or an arabinopyranose group, further can be -OH or In some embodiments, ^Ra is -OH. In some embodiments, ^Ra is a pyranose ring group, further can be an arabinopyranose group, further can be

In some embodiments, R ^b is -OH or methoxy (CH ₃ O—). In some embodiments, R ^b is -OH. In some embodiments, R ^b is methoxy.

In some embodiments, _R8 is R ^c is independently selected from any one of a trifluoroacetyl group, a trichloroacetyl group and a tribromoacetyl group.

In some embodiments, _R8 is ^Ra

In some embodiments, _R8 is

In the triterpene derivative of formula (I), R ₂ and R ₃ 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.

In some embodiments, R ₂ is -(CH ₂ ) ₂ -C(=O)-OR ₄ , and R ₃ is -CH(=CH ₂ )-CH ₃ .

_R4 can be selected from H, substituted or unsubstituted alkyl (alkyl can be _C1-6 alkyl), substituted or unsubstituted cycloalkyl (cycloalkyl can be _C3-6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (heterocycloalkyl can be _C3-6 heterocycloalkyl) and substituted or unsubstituted phenylalkyl (alkyl can be _C1-6 alkyl); wherein the ring-forming atoms in the heterocycloalkyl (such as _C3-6 heterocycloalkyl) include heteroatom _X1 , and the heteroatom _X1 can be selected from O and N, and further can be O. In the definition of _R4 , the number of heteroatom _X1 in heterocycloalkyl (such as _C3-6 heterocycloalkyl) can be one or more, for example, 1 or 2; in some embodiments, the number of heteroatom _X1 in heterocycloalkyl (such as _C3-6 heterocycloalkyl) is 1.

In the definition of R ₄ , in the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl may be independently substituted by one or more Q ₁ , any Q ₁ is independently selected from -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl (CH ₃ C(＝O)-), acetoxymethyl (CH ₃ C(＝O)-O-CH ₂ -), 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 may be 0 to 5, further 0 to 4, further 0 to 3, for example, 0, 1, 2, 3, 4 or 5.

In some embodiments, in the definition of R ₄ , 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 Q ₁ , and any Q ₁ is independently selected from -OH, -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl (CH ₃ C(＝O)-), acetoxymethyl (CH 3 C(＝O)-O-CH ₂ -), 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 selected from 1 to 5, further selected from 1 to 4, and further selected from 1 to 3, for example, 1, 2, 3, 4 or 5.

In some embodiments, in the definition of R ₄ , H in the divalent C _5-6 heterocycloalkyl in the substituted -[O-divalent C _5-6 heterocycloalkyl] _n -OH is replaced by one or more Q ₂ , any Q ₂ can independently be alkyl (optionally C _1-3 alkyl, further optionally -CH ₃ ) or -OH, and the number of alkyl and -OH in all Q ₂ can each independently be 1 to 4, further can be 1 to 3, for example 1, 2, 3 or 4.

In the definition of R ₄ , the ring atoms in the divalent C _5-6 heterocycloalkyl group include a heteroatom X ₂ , and the heteroatom X ₂ may be selected from O and N, and may further be O.

In the definition of Q ₁ , the number of the heteroatom X ₂ in the divalent C _5-6 heterocycloalkyl group can be one or more, for example, 1 or 2; in some embodiments, the number of the heteroatom X ₂ in the divalent C _5-6 heterocycloalkyl group is 1.

In some embodiments, in the definition of R ₄ , any Q ₁ is independently selected from -OH, -F, -Cl, -Br, -NH ₂ , -NO ₂ , 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 or a divalent furanose ring, Z contains -OH, n is 1, 2, 3, 4 or 5, and when n is greater than 1, adjacent -OZ- are connected by glycosidic bonds.

In some embodiments, R ₄ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl or phenyl C _1-6 alkyl; wherein the ring atoms in the C _3-6 heterocycloalkyl include a heteroatom X ₁ , wherein the heteroatom X ₁ is selected from O and N, and the number of the heteroatom X ₁ in the C _3-6 heterocycloalkyl is one or two.

In some embodiments, R ₄ is H, methyl, ethyl, or benzyl.

In some embodiments, the "substituted or unsubstituted -[O-divalent C _5-6 heterocycloalkyl] _n -OH" may also be -[OC _5-6 heterocycloalkyl (OH) _0-4 (CH ₃ ) _{0-4 ] n -OH} , where n is defined as above. Any "C _5-6 heterocycloalkyl" is a divalent group, wherein H may be independently substituted by 0 to 4 -OH groups, and may also be independently substituted by 0 to 4 methyl groups.

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, H in the six-membered carbocyclic ring may be substituted by one or more groups selected from the group consisting of _C1-3 alkyl (such as methyl, ethyl) and _R7 -O-.

_R7 may be the same as or different from _R4 .

In some embodiments, _R7 can be selected from H, substituted or unsubstituted alkyl (alkyl can be _C1-6 alkyl), substituted or unsubstituted cycloalkyl (cycloalkyl can be _C3-6 cycloalkyl) and substituted or unsubstituted heterocycloalkyl (heterocycloalkyl can be _C3-6 heterocycloalkyl) and substituted or unsubstituted phenylalkyl (alkyl can be _C1-6 alkyl); wherein the ring-forming atoms in the heterocycloalkyl (such as _C3-6 heterocycloalkyl) include heteroatom _X1 , and the heteroatom _X1 can be selected from O and N, and further can be O. In the definition of _R7 , the number of heteroatom _X1 in heterocycloalkyl (such as _C3-6 heterocycloalkyl) can be one or more, for example, 1 or 2; in some embodiments, the number of heteroatom X1 in heterocycloalkyl (such as _C3-6 heterocycloalkyl) is ₁ .

In the definition of R ₇ , in the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl may be independently substituted by one or more Q ₁ , any Q ₁ is independently selected from -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl (CH ₃ C(＝O)-), acetoxymethyl (CH ₃ C(＝O)-O-CH ₂ -), 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 may be 0 to 5, further 0 to 4, further 0 to 3, for example, 0, 1, 2, 3, 4 or 5.

In some embodiments, in the definition of R ₇ , in the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted phenylalkyl, H in the alkyl, cycloalkyl, heterocycloalkyl and phenylalkyl is independently substituted by one or more Q ₁ , and any Q ₁ is independently selected from -OH, -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl (CH _{3 C(＝O)-), acetoxymethyl (CH 3} C(＝O)-O-CH ₂ -), 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, and further can be selected from 1 to 3, for example, 1 _, 2, 3, 4 or 5.

In some embodiments, in the definition of R ₇ , H in the divalent C _5-6 heterocycloalkyl in the substituted -[O-divalent C _5-6 heterocycloalkyl] _n -OH may be replaced by one or more Q ₂ , any Q ₂ is independently alkyl (optionally C _1-3 alkyl, further optionally -CH ₃ ) or -OH, and the number of alkyl and -OH in all Q ₂ may each independently be 1 to 4, further may be 1 to 3, for example 1, 2, 3 or 4.

In the definition of R ₇ , the ring-forming atoms in the divalent C _5-6 heterocycloalkyl group include a heteroatom X ₂ , and the heteroatom X ₂ may be selected from O and N, and may further be O.

In the definition of R ₇ and Q ₁ , the number of the heteroatom X ₂ in the divalent C _5-6 heterocycloalkyl group may be one or more, for example, 1 or 2; in some embodiments, the number of the heteroatom X ₂ in the divalent C _5-6 heterocycloalkyl group is 1.

In some embodiments, in the definition of R ₇ , any Q ₁ is independently selected from -OH, -F, -Cl, -Br, -NH ₂ , -NO ₂ , 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 or a divalent furanose ring, Z contains -OH, n is 1, 2, 3, 4 or 5, and when n is greater than 1, adjacent -OZ- are connected by glycosidic bonds.

In some embodiments, any R ₇ 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 the ring atoms in the C _3-6 heterocycloalkyl include heteroatom X ₁ , and the heteroatom X ₁ is selected from O and N, and the number of heteroatom X ₁ in the C _3-6 heterocycloalkyl is one or more, for example, one or two; wherein, in the substituted C _1-6 alkyl, substituted C _3-6 cycloalkyl, substituted C _3-6 heterocycloalkyl substituted phenyl C _1-6 alkyl, H in C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl and phenyl C _1-6 alkyl is independently substituted by one or more Q ₁ , and any Q ₁ is independently selected from -OH, -F, -Cl, -Br, -NH ₂ , -NO ₂ , 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 or a divalent furanose ring, Z contains -OH, n is 1, 2, 3, 4 or 5, and when n is greater than 1, adjacent -OZ- are connected by glycosidic bonds connect.

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.

In some embodiments, _R7 is H, arabinopyranosyl, arabinofuranosyl or rhamnopyranosyl. It may further be arabinopyranosyl, arabinofuranosyl or rhamnopyranosyl.

In some embodiments, _R7 is H, arabinofuranosyl or rhamnopyranosyl. It may further be arabinofuranosyl or rhamnopyranosyl.

In some embodiments, R ₇ is

In some embodiments, R ₇ is

In some embodiments, R ₇ is

In some embodiments, in the triterpene derivative of formula (I), is -CH=CH- or -CH ₂ -CHR ₁ -;

_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

R ₂ is -(CH ₂ ) ₂ -C(＝O)-OR ₄ , R ₃ is -CH(＝CH ₂ )-CH ₃ , or R ₂ and R ₃ are both -(CR ₅ R ₆ ) ₂ -, and R ₂ , R ₃ and adjacent carbon atoms form a 6-membered saturated ring, and any R ₅ and any R ₆ are independently H, methyl or -OR ₇ ;

_R4 and any one of _R7 are independently selected from H, substituted or unsubstituted _C1-6 alkyl, substituted or unsubstituted _C3-6 cycloalkyl, substituted or unsubstituted _C3-6 heterocycloalkyl and substituted or unsubstituted _phenylC1-6 alkyl; wherein the ring atoms in the _C3-6 heterocycloalkyl include heteroatom _X1 , and the heteroatom _X1 is selected from O and N, and the number of the heteroatom _X1 in the _C3-6 heterocycloalkyl is one or more; in the substituted _C1-6 alkyl, substituted _C3-6 cycloalkyl, substituted _C3-6 heterocycloalkyl and substituted phenylC1-6 alkyl, H in the _C1-6 alkyl, _C3-6 cycloalkyl, _C3-6 heterocycloalkyl and _{phenylC1-6 alkyl} is independently substituted by one or more _Q1 , and any one of _Q1 is independently selected from -F, -Cl, -Br, _-NH2 , _-NO2 , acetyl, acetoxymethyl, C 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; in the substituted -[O-divalent C _5-6 heterocycloalkyl] _n -OH, the H in the divalent C _5-6 heterocycloalkyl is replaced by One or more Q ₂ are substituted, any Q ₂ is independently -CH ₃ or -OH, the number of -CH ₃ and -OH in all Q ₂ of the divalent C _5-6 heterocycloalkyl group is independently 1 to 4, the ring atoms in the divalent C _5-6 heterocycloalkyl group include heteroatoms X ₂ , the heteroatoms X ₂ is selected from O and N, the number of heteroatoms X ₂ in the divalent C _5-6 heterocycloalkyl group is one or more, and n is 0, 1, 2, 3, 4 or 5;

R ₈ is selected from:

wherein ^Ra and ^Rb are independently selected from H, -OH, substituted or unsubstituted _C1-6 alkyl, substituted or unsubstituted _C1-6 alkyl-O-, substituted or unsubstituted _C3-6 cycloalkyl-O- and substituted or unsubstituted C3-6 heterocycloalkyl-O-, wherein in the substituted _C1-6 alkyl, substituted _{C1-6 alkyl} -O-, substituted _C3-6 cycloalkyl-O- and substituted _C3-6 heterocycloalkyl-O-, H in the _C1-6 alkyl, _C1-6 alkyl-O-, _C3-6 cycloalkyl-O- and _C3-6 heterocycloalkyl-O- is independently substituted by one or more _Q3 , any one of _which is independently selected from: -OH, methyl, ethyl, acetyl, methoxy, ethoxy, -F, -Cl and -Br; the ring atoms in the _C3-6 heterocycloalkyl include heteroatom _X3 , wherein the heteroatom X3 is ^Rc is independently selected from any _one of trifluoroacetyl _, trichloroacetyl and tribromoacetyl.

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

R ₁ , R ₂ , R ₃ and R ₈ are as defined above, respectively.

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

wherein R ₁ , R ₅ , R ₆ , R ₇ and R ₈ are as defined above.

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);

R ₁ , R ₂ , R ₃ , R ₄ , R ₇ and R ₈ are respectively as defined above.

Based on any suitable embodiment of the present application, in some further embodiments, any C _1-6 alkyl group is independently a C _1-4 alkyl group, which can be further selected as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further selected as methyl or ethyl, further selected as methyl.

Based on any suitable embodiment of the present application, in some further embodiments, any C _3-6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Based on any suitable embodiment of the present application, in some further embodiments, any C _3-6 heterocycloalkyl group is independently oxirane, tetrahydropyranyl or tetrahydrofuranyl, and can further be tetrahydropyranyl or tetrahydrofuranyl.

Based on any suitable embodiment of the present application, in some further embodiments, any divalent C _5-6 heterocycloalkyl group is independently a divalent tetrahydropyranyl group or a divalent tetrahydrofuranyl group.

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

Any C _1-6 alkyl group is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and may further be methyl or ethyl, and may further be methyl;

Any C _3-6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

Any C _3-6 heterocycloalkyl group is independently oxirane, tetrahydropyranyl or tetrahydrofuranyl, and can further be tetrahydropyranyl or tetrahydrofuranyl;

Any divalent C _5-6 heterocycloalkyl group is independently a divalent tetrahydropyranyl group or a divalent tetrahydrofuranyl group.

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 in any of the aforementioned groups is acetylated.

Based on any suitable embodiment of the present application, in some further embodiments, the substituted or unsubstituted C _3-6 heterocycloalkyl is

Based on any suitable embodiment of the present application, in some further embodiments, the substituted or unsubstituted C _3-6 hetero The cycloalkyl group is selected from:

In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ia) or formula (Ic), and _R1 is a pyranose ring glycosyl or a furanose ring glycosyl. It can further be an arabinopyranose group or a rhamnopyranose group. It can further be

In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ib) or a compound of formula (Ic), and _R4 is H, _C1-3 alkyl or phenyl _C1-6 alkyl. Further, _R4 can be H.

In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); in R ₈ , ^Ra and ^Rb are independently H, -OH or methoxy.

In some embodiments, in the compound (Ia), R ₁ may be as defined above, and R ₁ may be optionally _R7 may be as defined above, and _R7 may be R ₈ is wherein R ^c is independently selected from any one of trifluoroacetyl, trichloroacetyl and tribromoacetyl; in some embodiments, R ₈ is

In some embodiments, in the compound (Ib), R ₄ is H, methyl, ethyl or benzyl (optionally H), and R ₈ is ^Ra can be as defined above, and ^Ra can be optionally

In some embodiments, in the compound (Ic), R ₁ is _R4 is H, methyl, ethyl or benzyl, _R8 is

In some embodiments, the triterpene derivative of formula (I) is compound (Ic), R ₁ is arabinopyranosyl or rhamnopyranosyl, and R ₁ can be _R4 is H or benzyl, _R8 is

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

R ₁ is a pyranose ring glycosyl or a furanose ring glycosyl (R ₁ may be arabinopyranose or rhamnopyranose);

R ₈ is

_R4 is H or benzyl.

In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); R ₁ is arabinopyranosyl or rhamnopyranosyl; R ₈ is _R4 is H or benzyl.

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

R ₁ is a pyranose ring glycosyl or a furanose ring glycosyl (R ₁ may be arabinopyranose or rhamnopyranose);

R ₈ is

_R4 is H or benzyl.

In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); R ₁ is arabinopyranosyl or rhamnopyranosyl; R ₈ is _R4 is H or benzyl.

In some embodiments, the triterpene derivative of formula (I) is a compound of formula (Ic); R ₈ is _R4 is H.

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

Compound C1: is a compound of formula (Ia), wherein R ₁ is _R7 is R ₈ is

Compound C2: is a compound of formula (Ia), wherein R ₁ is _R7 is R ₈ is

Compound C3: is a compound of formula (Ib), wherein R ₄ is H, R ₈ is ^Ra

C4 compound: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is

Compound C5: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is R ^b is methoxy.

C6 compound: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is R ^b is methoxy.

Compound C7: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is ^Ra is OH.

C8 compound: is a compound of formula (Ic), wherein R ₁ is (Right now ), R ₄ is H, R ₈ is

C9 compound: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is R ^b is OH.

Compound C10: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is R ^b is OH.

Compound C11: is a compound of formula (Ic), wherein R ₁ is _R4 is benzyl, _R8 is

C12 compound: is a compound of formula (Ic), wherein R ₁ is _R4 is methyl, _R8 is

Compound C13: is a compound of formula (Ic), wherein R ₁ is _R4 is ethyl, _R8 is

Compound C14: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is

Compound C15: is a compound of formula (Ic), wherein R ₁ is _R4 is H, _R8 is

C16 compound: is a compound of formula (Ia), wherein R ₁ is _R7 is R ₈ is

Compound C17: is a compound of formula (Ia), wherein R ₁ is _R7 is R ₈ is

C18 compound: is a compound of formula (Ib), wherein R ₄ is benzyl, R ₈ is ^Ra

Compound C19: is a compound of formula (Ib), wherein R ₄ is methyl, R ₈ is ^Ra

The triterpene derivatives of formula (I) can be obtained by separation and purification from the natural plant Cyclocarya paliurus (such as compounds C1 to C10), or can be obtained by structural optimization based on the isolated triterpene derivatives (such as compounds C11 to 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 for 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). The pharmaceutically acceptable salts of the triterpene derivatives of formula (I) can be prepared by conventional salt-forming methods in the art, such as, but not limited to, cooling crystallization method, anti-solvent method, etc.

In traditional technology, Cyclocarya paliurus is believed to have the effects of clearing away heat and relieving summer heat, lowering blood sugar and blood pressure. Research in recent years has also focused on the hypoglycemic pharmacology and material basis of the efficacy of Cyclocarya paliurus. In this application, some triterpene derivatives are obtained from the Cyclocarya paliurus leaf extract through a specific separation and purification method, and then new triterpene derivatives are derived. The separation and purification method used in this application has a higher extraction efficiency.

The applicant of the present application has unexpectedly discovered through a large number of experimental explorations that the triterpene derivatives of formula (I) have a strong killing effect 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 Enterococcus, Pseudomonas aeruginosa, Mycobacterium abscessus, Klebsiella pneumoniae and Helicobacter pylori. The triterpene derivatives of formula (I) still have high bactericidal activity against some antibiotic-resistant strains, such as: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus and linezolid-resistant Enterococcus.

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.

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

In some embodiments, compound C8 and compound C11 can be used for applications targeting bacteria such as streptococci (such as group A/B hemolytic streptococci and streptococci pneumoniae) and staphylococci (such as methicillin-resistant/sensitive Staphylococcus aureus and Staphylococcus epidermidis). It can be used for skin and soft tissue infections, respiratory tract infections, heart valve infections, and bone and joint infections, but is not limited thereto. In some embodiments, compound C11 has a slightly stronger killing effect on staphylococci than compound C8.

In some embodiments, compound C14 has a killing effect on streptococci (such as A/B hemolytic streptococci and Streptococcus 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.). The killing effect of compound C14 on Escherichia coli is stronger than that of compound C8 and compound C11. In addition, compound C14 also has a certain killing effect on Enterococcus faecalis, vancomycin-resistant Enterococcus and linezolid-resistant Enterococcus. 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 and other aspects.

In some embodiments, compound C15 can have 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 infection.

In some embodiments, relative to Lactobacillus acidophilus, the triterpene derivatives of formula (I) are effective 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, The antibacterial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus all showed a certain degree of selectivity.

In the present application, MIC (Minimal Inhibitory Concentration) can be used to characterize the antibacterial ability. The lower the MIC value, the lower the effective antibacterial concentration and the stronger the antibacterial effect. The triterpene derivatives of formula (I) in the present application can achieve antibacterial effects by targeting FtsZ.

The bacterial division Z ring is a ring structure formed by the filamentous temperature-sensitive mutant Z (FtsZ) at the cell division site. It is the basic structure for bacteria to survive and proliferate. Because it exists in most bacterial species, is highly conserved, and plays a decisive role in cell division, cell wall formation, cell morphology and structural stability, it can be used as a potential target for new antibiotics. Although a very small number of compounds that act on FtsZ have been successfully synthesized, such as PC190723, there are no antibacterial drugs targeting FtsZ on the market worldwide due to poor drugability and high toxicity.

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 unable to complete division after nucleic acid replication, and finally 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 efficacy of treating infections caused by drug-resistant bacteria.

Mammalian cells do not secrete FtsZ. Therefore, it can be considered that the triterpene derivatives of formula (I) have no known toxic side effects in the human body. In addition, the triterpene derivatives of formula (I) are derived from natural plants that are both edible and medicinal, and have the advantage of good drugability.

The top and bottom structures of FtsZ protein have significant geometric complementarity. In the polymer state, a wide hydrophobic interaction area 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. Its pocket volume is Has a surface area of Depth up to Theoretically, FtsZ has 17 donor units and 34 acceptor units that form hydrogen bonds, and 20 hydrophobic binding sites. The hydrophilic/hydrophobic ratio is 0.28. The schematic diagram of the binding pocket of FtsZ can be found in Figure 3, where the light-colored part is the binding pocket area.

Molecular docking showed 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, and its binding mode may be similar to the reported crystal structure of the complex of FtsZ and GTP (PDB ID: 5MN5).

Taking compound C8 and compound C11 as examples, Figures 1A-1B and 2A-2B are schematic diagrams of the binding modes of compound C8 and compound C11 with FtsZ, respectively. Figure 1A is a visualization schematic diagram 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 schematic diagram of the docking of compound C11 with FtsZ, and Figure 2B is a surface diagram of the interaction between compound C11 and FtsZ.

See Figures 1A-1B and Table 4. Molecular docking showed that compound C8 could deeply insert into the GTP binding pocket of FtsZ, and form hydrogen bonds with amino acid residues Gly108, Thy109, Glu139 and ASN166 of Ftsz protein to interact with each other, bind to each other through hydrophobic interaction between amino acid residues Asp46, Pro135 and Phe183, and bind to each other through ionic bonds between amino acid residues Arg143. The analysis results showed that the docking index of compound C8 with FtsZ was -5.593, which was equivalent to the docking index of natural ligand GTP with FtsZ -5.612. It is speculated that compound C8 competitively binds to the GTP binding site of FtsZ, causing FtsZ to lose its GTPase activity and fail to catalyze GTP to form Z ring, which ultimately leads to bacterial death.

PC190723 is the most studied compound targeting FtsZ. The binding site of this compound 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, after the binding of compounds C8 and PC19023 to FtsZ, the GTPase activity of FtsZ is inhibited. The difference between the triterpene derivatives of formula (Ib), the triterpene derivatives of formula (Ic) and the triterpene derivatives of formula (Ia) is that the triterpene derivatives of formula (Ib) and (Ic) are open-ring tetracyclic triterpene derivatives, and the triterpene derivatives of formula (Ia) are tetracyclic triterpene derivatives with a complete structure. Among the compounds contained in the plant Cyclocarya paliurus, the open-ring tetracyclic triterpene derivatives usually have a carboxyl group, contain active hydrogen, are easy to form hydrogen bonds, and can It can help stabilize this bond and achieve better antibacterial effect.

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.

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

In some embodiments, some triterpene derivatives are extracted from Cyclocarya paliurus, such as compounds C1-C10.

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

The present application provides a method for separating and purifying triterpene derivatives from Cyclocarya paliurus, and also provides a method for modifying the groups of the extracted triterpene derivatives by chemical reaction. The following method 1 or method 2 may be used.

Method 1, separation and purification of triterpene derivatives from Cyclocarya paliurus: shade-dried Cyclocarya paliurus leaves are subjected to reflux extraction twice with 10 times the weight of ethanol, the filtrates are combined, concentrated and dried, mixed with silica gel, and then dry-loaded on a silica gel column for gradient elution to obtain compounds, wherein the elution solvent can be selected from one or more of the following solvents: dichloromethane, methanol, water, petroleum ether and ethyl acetate. The triterpene derivatives obtained by method 1 can be recorded as "extract compounds".

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

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.

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

The above-mentioned compounds provided in the present 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.

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

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

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

In the present application, "antibacterial ingredient" refers to an ingredient with antibacterial effect; "non-antibacterial ingredient" refers to an ingredient without antibacterial effect. Non-antibacterial ingredients may have other physiological and/or pharmacological functions and may also be excipients.

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.

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.

In this application, "antimicrobial composition" refers to a composition with antimicrobial effect. "Antibacterial composition" can be used for medical purposes, such as for treating or improving bacterial infection, or for non-medical purposes, such as for cleaning and sterilizing daily environmental items, or for improving the antimicrobial ability of specific products, such as making antimicrobial products, etc.

In some embodiments, the triterpene derivatives of formula (I) and antibacterial compositions containing the same, in addition to their 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.

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, mucosal, and lumen washing solutions.

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 infection, and can also be used in veterinary preparations for the treatment of bacterial infection. 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. If not specifically limited, relevant management specifications refer to the current specifications at the time of production.

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.

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.

In the present application, "antibacterial drug" and "antibacterial drug composition" refer to a pharmaceutical composition having an antibacterial effect.

In this application, "drug" includes any agent, compound, composition or mixture that provides a pharmacological effect in vivo or in vitro, and often provides a beneficial effect. The scope of the pharmacological effect of the "drug" in vivo is not particularly limited, and it can be a systemic effect or only a local effect. The activity of the "drug" is not particularly limited, and it can be an active substance that can interact with other substances, or it can be an inert substance that does not interact.

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

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.

In this application, "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, isotonic 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, etc. 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 buffered saline; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

In the present application, the "carrier" may include, but is not limited to, mannitol, sorbitol, sodium pyrosulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium ethylenediaminetetraacetate (disodium EDTA), calcium sodium 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.

It should be understood that "pharmaceutically acceptable carriers" can be selected from substances that are allowed to be added in relevant management regulations, and further, do not include substances that are prohibited from being added in relevant management regulations. If not specifically limited, relevant management regulations refer to the current regulations at the time of production.

The present application also provides the use of the triterpene derivative of formula (I) or a pharmaceutically acceptable salt thereof in a drug for preventing and treating bacterial infection.

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.

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 a disease caused by bacterial infection.

In some embodiments, the disease caused by the bacterial infection includes a disease caused by a drug-resistant bacterial infection. Diseases caused by drug-resistant bacterial infections include diseases caused by at least one of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, and linezolid-resistant Enterococci.

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

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

In some embodiments, the subject is a mammal.

In some embodiments, the subject may be a patient who has already suffered from a bacterial infection, or may be a person 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.

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 and further used for the treatment of bacterial infection.

In the present application, "therapeutically effective amount" refers to the amount of a pharmaceutically 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 pharmaceutically active ingredient that brings a pharmacologically positive effect to an individual, wherein 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.

The administration method may include, but is not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, topical administration, and inhalation. Taking the oral administration method as an example, the corresponding oral preparation may be, but is not limited to, oral preparations, such as mouthwash, toothpaste, skin, mucosa, lumen washing liquid, etc. Taking the topical administration method as an example, the corresponding preparation may be a cream, ointment, patch or spray suitable for application to the skin, etc.

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

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.

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

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 supplies, bedding, kitchen utensils, dining utensils, toys, etc.

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.

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

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.

In some embodiments, the use may be for therapeutic purposes.

In some embodiments, the application is for non-diagnostic and therapeutic purposes. For example, it can be used as a reference compound for antibacterial drug screening, and can also be used as a functional material in daily necessities, packaging supplies, household appliances, environmental materials, building materials and coatings, etc. It can also be used in antibacterial films, touch surfaces of electrical appliances, water treatment products, sanitary ceramics, antibacterial coatings and other materials or products.

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

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.

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 Enterococcus, linezolid-resistant Enterococcus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus.

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.

In some embodiments, the use may be for therapeutic purposes.

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

In some embodiments, the triterpene derivative of formula (I) or its pharmaceutically acceptable salt or solvate has a killing effect on any one, any two or all of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and linezolid-resistant Enterococcus. In some embodiments, the triterpene derivative of formula (I) or its pharmaceutically acceptable salt or solvate 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.

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:

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

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

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.

Some specific embodiments are provided below.

The embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application 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 manual or normal conditions in this area, can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

In the following specific embodiments, 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 test accuracy or operation accuracy are allowed.

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

Unless otherwise specified, "80% ethanol" means a mixed solvent in which ethanol accounts for 80% by volume and water accounts for 20% by volume.

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

If not 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.

1. Preparation of Cyclocarya paliurus triterpenoid derivatives

(I) Extraction and preparation of triterpene derivatives 1-10 of Cyclocarya paliurus

Weigh 5 kg of room temperature dried Cyclocarya paliurus leaves, crush them, add 10 times the weight of 80% ethanol, reflux and extract at 50°C for 1 hour, filter the residue and extract 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 then dry load on a 3000 g silica gel column, dichloromethane-methanol (90%-0%) gradient elution, that is, gradient elution from dichloromethane:methanol volume ratio of 90%:10% to 0%:100%, elution volume of 3 column volumes, and obtain 6 fractions (Fr.1～6). Fr.1 (55 g) was placed on a 800 g silica gel column and gradient eluted with petroleum ether-ethyl acetate (100%-20%, i.e., from petroleum ether:ethyl acetate volume ratio of 100%:0% to 20%:80%), with an elution volume of 3 column volumes, to obtain 5 fractions (Fr.1a～e). Fr.1b (2 g) was repeatedly subjected to C18 preparative chromatography with methanol-water (20%-100%, i.e., from methanol:water volume ratio of 20%:80% to 100%:0%) gradient elution, with an elution volume of 4 column volumes, to obtain compound C5 (208 mg) and compound C6 (112 mg). Fr.2 (62 g) was subjected to a 800 g silica gel column and gradient eluted with petroleum ether-ethyl acetate (80%-20%, i.e., from petroleum ether:ethyl acetate volume ratio of 80%:20% to 20%:80%), with an elution volume of 3 column volumes, to obtain 5 fractions (Fr.2a-e). Fr.2b (3 g) was repeatedly subjected to C18 preparative chromatography with methanol-water (20%-100%, i.e., from methanol:water volume ratio of 20%:80% to 100%:0%) gradient elution, with an elution volume of 4 column volumes, to obtain compound C7 (230 mg) and compound C8 (183 mg). Fr.3 (80 g) was subjected to 800 g silica gel column and gradient eluted with petroleum ether-ethyl acetate (80%-20%, i.e., from petroleum ether:ethyl acetate volume ratio of 80%:20% to 20%:80%) in 3 column volumes to obtain 4 fractions (Fr.3a-d). Fr.2c (2 g) was repeatedly subjected to C18 preparative chromatography with methanol-water (20%-100%, i.e., from methanol:water volume ratio of 20%:80% to 100%:0%) and gradient eluted in 4 column volumes to obtain 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 petroleum ether:ethyl acetate volume ratio of 70%:30% to 10%:90%) in 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 methanol:water volume ratio of 20%:80% to 100%:0%) and gradient eluted in 4 column volumes to obtain compound C1 (103 mg) and compound C2 (120 mg).

Each fraction can be identified by mass spectrometry (MS), hydrogen nuclear magnetic resonance ( ¹ H NMR) and carbon nuclear magnetic resonance ( ¹³ C NMR), and can also be combined with other known structural analysis methods in the field of organic chemistry. Taking compound C3 and compound C8 as examples, the following provides ¹ H NMR and ¹³ C NMR test data.

Compound C1: 20,24-Epoxydammarane (-3β,12β,24R)-12-O-α-L-rhamnopyranosyl-25-hydroxy-3-O-α(-5′-O-acetyl)-L-furanoside.

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).

Compound C3: Cyclocarya paliurus glycoside 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, easily soluble in organic solvents such as ethanol, methanol, acetonitrile, Liebermann-Burchard reaction positive, MS m/z: 603.81 [MH] ^- , ¹ ＨNMR (DMSO-d6, 400 MHz) and ¹³ C NMR (DMSO-d6, 100 MHz), the structural characterization parameters of compound C3 can be seen in Table 1.

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)-en,3-oic acid).

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).

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).

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

Compound C8: Cyclocarya paliurus glycoside 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, easily soluble in organic solvents such as ethanol, methanol, and acetonitrile The Liebermann-Burchard reaction was positive, MS m/z: 617.55 [MH] ^- , ¹ Ｈ NMR (DMSO-d6, 400 MHz) and ¹³ C NMR (DMSO-d6, 100 MHz), the structural characterization parameters of compound C8 can be seen in Table 1.

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-didamara-4(28),23-dien-3-oic acid 12-O-β-D-quinovopyranoside).

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).

Table 1. ¹ H NMR and ¹³ C NMR data of compound C3 and compound C8

(II) Synthesis of Compound C11

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), and 2-3 times the molar equivalent of DMAP or DIEA were added as appropriate. The reaction was allowed to proceed for about 10 h at room temperature, and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the mixture 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 product (compound C11) with a yield of 93.5%.

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

MS m/z: 695.4441 [M+H] ⁺ .

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).

¹³ C-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. 84,66.44,51.19,50.51,49.49,49.04,44.56,43.98,40.52,36.86,34.73,32.84,3 0.92,29.69,27.14,25.99,24.93,24.14,20.20,19.04,18.36,16.69,16.65,15.68.

(III) Synthesis and preparation of compound C12

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). Add 2-3 times the molar equivalent of DMAP or DIEA as needed. React at room temperature for about 10 hours, and monitor the reaction by TLC. After the reaction is completed, wash three times with 5% hydrochloric acid 5mL, three times with 5% sodium bicarbonate 5mL, three times with water 10mL, and three times with saturated sodium chloride 10mL. The organic phase is 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 product (Compound C12) with a yield of 94.8%.

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

MS m/z: 633.4291 [M+H] ⁺ .

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),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).

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 .19,50.51,49.49,49.04,44.56,43.98,40.52,36.86,34.73,32.84,30.92,2 9.69,27.14,25.99,24.93,24.14,20.20,19.04,18.36,16.69,16.65,15.68.

(IV) Synthesis and preparation of compound C13

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), and 2-3 times the molar equivalent of DMAP or DIEA were added as appropriate. The reaction was allowed to proceed for about 10 h at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the mixture 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 product (compound C13) with a yield of 94.3%.

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

MS m/z: 647.4448 [M+H] ⁺ .

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).

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.

(V) Synthesis of Compound C14

Compound C8 (6 mg, 10 μmol) and isopentene (0.70 mg, 10 μmol) were added to 1 mL of dichloromethane and dissolved; 10 μL of dimethylaluminum chloride (1.0 M, 10 μmol) was slowly added to the reaction solution at 0°C. The reaction was carried out at 0°C for about 10 hours, and the reaction was quenched with water. After the reaction was completed, 3 mL of ether was used for extraction three times, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (mixed solvent of n-hexane/ethyl acetate, volume ratio of 50:1 to 10:1) to obtain 5.2 mg of product (compound C14) with a yield of 75.4%.

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

MS m/z: 689.4917 [M+H] ⁺ .

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).

¹³ C-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.

(VI) Synthesis and preparation of compound C15

Compound C8 (6 mg, 10 μmol) and vinyl methyl ketone (0.70 mg, 10 μmol) were added to 1 mL of dichloromethane and dissolved; 10 μL of dimethylaluminum chloride (1.0 M, 10 μmol) was slowly added to the reaction solution at 0°C. The reaction was carried out for about 10 hours at 0°C, and the reaction was quenched with water. After the reaction was completed, 3 mL of ether was used for extraction three times, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (mixed solvent of n-hexane/ethyl acetate, volume ratio of 50:1 to 10:1) to obtain 5.3 mg of product (compound C15) with a yield of 76.8%.

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

MS m/z: 689.4552 [M+H] ⁺ .

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),2.22(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).

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. 04,44.56,43.98,40.52,36.86,34.73,34.84,32.84,32.55,30.92,30.72,29.6 9,27.14,25.99,25.63,24.93,24.14,22.67,20.20,18.36,16.69,16.65,15.68.

(VII) Synthesis and preparation of compound C16

Trifluoroacetic anhydride (1.09 mL of 0.5 M dichloromethane solution, 0.545 mmol) was added dropwise to 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 heated to 0 °C over 90 minutes, and the reaction solution was stirred at 0 °C for another 20 minutes. The reaction solution was then quenched with 1N HCl aqueous solution. The reaction solution was diluted with n-hexane, stirred vigorously, and heated to room temperature. The aqueous phase was extracted three times with n-hexane, and the organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The product was purified by rapid column chromatography on silica gel (n-hexane/ethyl acetate mixed solvent, volume ratio of 100:1 to 10:1) to obtain 29 mg of product (compound C16) with a yield of 64.4%.

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

MS m/z: 892.4798 [M+H] ⁺ .

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)

¹³ C-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 0.7,38.1,52.7,55.6,39.1,36.3,25.5,35.2,38.7,18.5,114.6,155.7,17 0.2,82.8,62.5,26.9,18.5,17.0,18.8,16.1,23.7,23.7,20.7,22.7,22.7.

(VIII) Synthesis and preparation of compound C17

Trifluoroacetic anhydride (1.09 mL of a 0.5 M solution in dichloromethane, 0.545 mmol) was added dropwise to 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 heated to 0 °C over 90 minutes, and the reaction mixture was stirred at 0 °C for another 20 minutes. The reaction mixture was then quenched with 1N aqueous HCl. The reaction mixture was diluted with n-hexane, stirred vigorously, and heated to room temperature. The aqueous phase was extracted three times with n-hexane, and the organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The product was purified by rapid column chromatography on silica gel (n-hexane/ethyl acetate mixed solvent, volume ratio of 100:1 to 10:1) to obtain 25 mg of the product (compound C17), yield 58.1%.

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

MS m/z:864.4849[M+H] ⁺ .

¹ H-NMR(400MHz, DMSO-d6)δ:

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)

¹³ C-NMR (100MHz, DMSO-d6) δ:

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.

(IX) Synthesis and preparation of compound C18

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), and 2-3 times the molar equivalent of DMAP or DIEA were added as appropriate. The reaction was allowed to proceed for about 10 h at room temperature, and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the mixture 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 product (compound C18) with a yield of 89.8%.

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

MS m/z: 694.4448 [M+H] ⁺ .

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)

¹³ C-NMR (100MHz, DMSO-d6) δ: 51.0, 40.7, 50.4, 34.1, 33.1, 107.9, 66.5, 73 .9,70.5,77.2,128.3,40.2,136.1,135.8,127.1,127.1,128.9,128.9,12 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.

(X) Synthesis and preparation of compound C19

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), and 2-3 times the molar equivalent of DMAP or DIEA were added as appropriate. The reaction was allowed to proceed for about 10 h at room temperature, and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the mixture 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 product (compound C19) with a yield of 90.3%.

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

MS m/z: 618.4133 [M+H] ⁺ .

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),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)

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.

Test on the killing effect of diterpenoid and triterpenoid derivatives on bacteria

1. Strains and drugs

Strains: Vancomycin-resistant Enterococci (VRE), linezolid-resistant Enterococci, Methicillin-resistant Staphylococcus Aureus (MRSA), Mycobacterium abscessus, Helicobacter pylori, and Klebsiella pneumoniae were isolated from 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). Common Staphylococcus aureus (ATCC25923), Escherichia coli ATCC25922, Staphylococcus epidermidis ATCC8099, Staphylococcus saprophyticus, Streptococcus pneumoniae ATCC6303, alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus, Lactobacillus acidophilus ATCC4356, Enterococcus faecalis ATCC BAA-1240, Mycobacterium abscessus and Pseudomonas aeruginosa PA14 were all purchased.

Drugs: the triterpene derivatives (compounds C1-C15) prepared above, penicillin sodium, oxacillin sodium and vancomycin hydrochloride (purchased from the market).

(II) Bacterial culture

Culture medium: The culture medium for common Staphylococcus aureus (ATCC25923), MRSA-1, MRSA-2, MRSA-3, MRSA-4, MRSA-5, Staphylococcus epidermidis, Staphylococcus saprophyticus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae is MHB (Mueller-Hinton Broth). Streptococcus pneumoniae, alpha-hemolytic streptococci and beta-hemolytic streptococci are cultured in MHB medium containing 5% serum. Lactobacillus acidophilus ATCC4356 is cultured in MRS medium. Enterococcus faecalis, vancomycin-resistant enterococci and linezolid-resistant enterococci are cultured in trypticase soy broth medium containing 0.6% yeast extract. Culture conditions: 37°C, 150rpm shaking culture. Helicobacter pylori is cultured in Helicobacter pylori medium at 37°C in an incubator containing 5% O ₂ , 5% CO _2. Mycobacterium abscessus is cultured in Roche basal medium at 30°C.

(III) Test on the bactericidal effect of triterpene derivatives

Preparation of test bacteria: Inoculate each bacterium in 5 mL of the corresponding culture medium, culture overnight at 37°C in a shaking incubator, adjust the McFarland 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.

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 7.5 mg/mL triterpene derivative mother solution.

Preparation of triterpene derivative drug concentration gradient: Take the drug mother solution and dilute it with the corresponding culture medium so that the initial concentration of the triterpene derivative is 300μg/mL, take 100μL of the above drug solution and add it to the 1st and 2nd wells of the 96-well plate. From the 2nd well, add 100μL of culture medium and dilute it to the 9th well in a continuous manner. Set the 10th well as the culture medium control. From the 1st to the 9th well, the concentrations of triterpene derivatives are 150μg/mL, 75μg/mL, 37.5μg/mL, 18.75μg/mL, 9.375μg/mL, 4.6875μg/mL, 2.34375μg/mL, 1.171875μg/mL, 0.5859375μg/mL.

Test of antibacterial effect: 100 μL of the bacterial solution prepared above was added to the wells of each concentration of triterpene derivatives and the wells of the culture medium control. After thorough mixing, the mixture was incubated overnight at 37°C in a humidified box. The test value of the lowest drug concentration at which no colonies grew was determined as the MIC (minimum inhibitory concentration).

If none of the above concentrations can achieve “no colony growth”, the MIC will be recorded as “>150 μg/mL”.

MIC can be used to characterize antibacterial ability. The lower the MIC value, the lower the effective antibacterial concentration and the stronger the antibacterial effect.

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

(IV) Test results

According to Table 2 to Table 4, it can be seen that 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. And 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 a 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.

In addition, it can be seen from Tables 2 to 4 that although C0 and C4-C15 have similar core structures, some of the compounds have better killing effects on some key strains through different R ₁ , R ₄ and R ₈ . For example, C0 had no inhibitory effect on vancomycin-resistant Enterococcus, linezolid-resistant Enterococcus and Klebsiella pneumoniae at the highest concentration tested, but among C4-C15, C5 had a significantly stronger inhibitory effect on the above bacteria than C0.

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

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

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

The chemical formula of C0 in Table 4 is:

Analysis of the antibacterial mechanism of diterpenoid and triterpenoid derivatives

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 Glide in the software package was performed in its SP mode, LigPrep was used to pre-treat the ligand compounds under default parameters, and Protein preparation was used to pre-treat the protein complexes. After docking, the obtained docking results were analyzed using PyMol software.

The "docking score" of each compound and FtsZ represented by Staphylococcus aureus is used to characterize the binding strength of the compound to FtsZ. The larger the negative value of the docking score, the stronger the binding strength between the compound and FtsZ.

The test results can be found in Table 4.

The negative value of the docking score of compound C15 is the largest, indicating that it has the strongest binding force with FtsZ and relatively stronger killing effect on various bacteria, which is consistent with the test results in Tables 2 and 3. This may be because compound C15 has a carboxyl group, and when the electron-withdrawing group ketocarbonyl is introduced into R ₈ , compound C15 can form hydrogen bond interactions with Gly110 and Asn44 of the GTP binding domain of FtsZ, making compound C15 have a stronger binding force with FtsZ.

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.

The binding force between compounds C12 and C13 and FtsZ is relatively weak, which may be due to the disappearance of active hydrogen when R ₄ is methyl or ethyl, and the inability to form hydrogen bonds.

Compound C0 had no inhibitory effect on vancomycin-resistant Enterococcus, linezolid-resistant Enterococcus, and Klebsiella pneumoniae at the highest concentration tested. The possible reasons for this are that, on the one hand, the glycoside of compound C0 is arabinopyranoside, and the glycoside of C8 is rhamnopyranoside. Rhamnopyranose is easier to pass through the bacterial cell membrane than arabinopyranose to reach the bacterial cytoplasm and bind to FtsZ; on the other hand, the docking score of compound C0 with FtsZ is -4.955, while the docking score of C8 with FtsZ is -5.593. The binding ability of compound C0 with FtsZ is weaker than that of C8. Based on C8, C11, C14, and C15 were obtained by chemical synthesis, which increased the binding ability of the compound with FtsZ and enhanced the antibacterial ability. The difference in glycosides leads to different binding forces, which also suggests different antibacterial effects.

Table 4. Molecular docking results (binding strength)

In addition, due to the different amino acid sequences and protein structures of FtsZ of different bacteria, the same compound may have different antibacterial activities against different bacteria. For example, the sequence similarity between FtsZ of Staphylococcus aureus and FtsZ of Pseudomonas aeruginosa is only 53%. Compound C0 can inhibit the growth of Staphylococcus aureus, but has no effect on the growth of Pseudomonas aeruginosa. In view of this phenomenon, a molecular docking simulation experiment was also conducted on the docking score of compound C0 and FtsZ of Pseudomonas aeruginosa. By analyzing the data of the experimental results, it was found that the docking score of compound C0 with FtsZ of Pseudomonas aeruginosa was -1.005, and the binding ability with FtsZ of Pseudomonas aeruginosa was poor. There is a significant difference between R ₈ of compound C5 and C0, which makes C5 not only able to inhibit the growth of Staphylococcus aureus, but also inhibit the growth of Pseudomonas aeruginosa. Through molecular docking analysis, the docking score of C5 with FtsZ of Pseudomonas aeruginosa was -2.115, and the binding ability was enhanced compared with compound C0, so C5 also showed a growth inhibitory effect on Pseudomonas aeruginosa.

The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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.

The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims.

Claims (44)

A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof,
in, is -CH=CH- or -CH ₂ -CHR ₁ -; _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; R ₂ is -(CH ₂ ) ₂ -C(=O)-OR ₄ and R ₃ is -CH(=CH ₂ )-CH ₃ , or R ₂ and R ₃ are both -(CR ₅ R ₆ ) ₂ - and R ₂ and R ₃ form a saturated 6-membered ring with adjacent carbon atoms; Any one of R ₅ and any one of R ₆ are independently H, methyl or -OR ₇ ; R ₄ and any one of R ₇ 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 the ring atoms in the C _3-6 heterocycloalkyl include heteroatom X ₁ , and the heteroatom X ₁ is selected from O and N, and the number of the heteroatom X ₁ in the C _3-6 heterocycloalkyl is one or more; In substituted C _1-6 alkyl, substituted C _3-6 cycloalkyl, substituted C _3-6 heterocycloalkyl and substituted phenyl C _1-6 alkyl, H in C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl and phenyl C _1-6 alkyl is independently substituted by one or more Q ₁ , and any Q ₁ is independently selected from -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl, CH ₃ C(＝O)-O-CH ₂ -, 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; In the substituted -[O-divalent C _5-6 heterocycloalkyl] _n -OH, H in the divalent C _5-6 heterocycloalkyl is replaced by one or more Q ₂ , any Q ₂ is independently -CH ₃ or -OH, the number of -CH ₃ and -OH in all Q ₂ of the divalent C _5-6 heterocycloalkyl is independently 1 to 4, the ring atoms in the divalent C _5-6 heterocycloalkyl include heteroatom X ₂ , the heteroatom X ₂ is selected from O and N, the number of heteroatom X ₂ in the divalent C _5-6 heterocycloalkyl is one or more, and n is 0, 1, 2, 3, 4 or 5; R ₈ is selected from: wherein ^Ra and ^Rb are independently selected from H, -OH, substituted or unsubstituted _C1-6 alkyl, substituted or unsubstituted _C1-6 alkyl-O-, substituted or unsubstituted _C3-6 cycloalkyl-O- and substituted or unsubstituted C3-6 heterocycloalkyl-O-, wherein in substituted _C1-6 alkyl, substituted _C1-6 alkyl-O-, substituted _C3-6 cycloalkyl-O- and substituted _C3-6 heterocycloalkyl-O-, H in _C1-6 alkyl, _C1-6 alkyl-O-, _C3-6 cycloalkyl-O- and _C3-6 heterocycloalkyl- _O- is independently substituted by one or more _Q3 , any _Q3 is independently selected from: -OH, methyl, ethyl, acetyl, methoxy, ethoxy, -F, -Cl and -Br; the ring atoms in _C3-6 heterocycloalkyl include heteroatom _X3 , and the heteroatom _X3 is selected from O and N; R ^c is independently selected from any one of a trifluoroacetyl group, a trichloroacetyl group and a tribromoacetyl group. The compound or pharmaceutically acceptable salt or solvate thereof according to claim 1, characterized in that the compound represented by formula (I) is a compound of formula (II) or a compound of formula (III):
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that R ₁ is selected from and any of the aforementioned groups wherein one -OH group is acetylated. The compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, characterized in that: R ₄ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl or phenyl C _1-6 alkyl; wherein the ring atoms in the C _3-6 heterocycloalkyl include a heteroatom X ₁ , and the heteroatom X ₁ is selected from O and N, and the number of the heteroatom X ₁ in the C _3-6 heterocycloalkyl is one or two; Any one of R ₇ 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 the ring atoms in the C _3-6 heterocycloalkyl include heteroatoms X ₁ , and the heteroatoms X ₁ are selected from O and N, and the number of the heteroatoms X ₁ in the C _3-6 heterocycloalkyl is one or more; Wherein, in the substituted C _1-6 alkyl, substituted C _3-6 cycloalkyl, substituted C _3-6 heterocycloalkyl and substituted phenyl C _1-6 alkyl, H in the C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl and phenyl C _1-6 alkyl is independently substituted by one or more Q ₁ , wherein any one of Q ₁ is independently selected from -OH, -F, -Cl, -Br, -NH ₂ , -NO ₂ , acetyl, CH ₃ C(=O)-O-CH ₂ -, C _1-6 alkyl, C _1-6 alkyl-O-, C _3-6 cycloalkyl-O-, and substituted or unsubstituted -[OZ] _n -OH, Among them, -O-Z- is a divalent pyranose ring group or a divalent furanose ring group, Z contains -OH, n is 1, 2, 3, 4 or 5, and when n is greater than 1, adjacent -O-Z- are connected by glycosidic bonds. The compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 4, characterized in that any C _1-6 alkyl group is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; Any C _3-6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Any C _3-6 heterocycloalkyl group is independently oxirane, tetrahydropyranyl or tetrahydrofuranyl; Any divalent C _5-6 heterocycloalkyl group is independently a divalent tetrahydropyranyl group or a divalent tetrahydrofuranyl group. The compound according to claim 5 or a pharmaceutically acceptable salt or solvate thereof, characterized in that the substituted or unsubstituted C _3-6 heterocycloalkyl is Or the aforementioned group in which one -OH is acetylated. The compound according to claim 5 or a pharmaceutically acceptable salt or solvate thereof, characterized in that The substituted or unsubstituted C _3-6 heterocycloalkyl group is The compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7, 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);
The compound or pharmaceutically acceptable salt or solvate thereof according to claim 8, characterized in that the compound represented by formula (I) is a compound of formula (Ib) or a compound of formula (Ic), and R ₄ is H, C _1-3 alkyl or benzyl. The compound according to claim 9 or a pharmaceutically acceptable salt or solvate thereof, characterized in that _R4 is H. The compound or pharmaceutically acceptable salt or solvate thereof according to claim 8, characterized in that the compound represented by formula (I) is a compound of formula (Ia) or a compound of formula (Ic), and _R1 is a pyranose ring syl group or a furanose ring syl group. The compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, characterized in that _R1 is arabinopyranosyl or rhamnopyranosyl. The compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, characterized in that R ₁ is The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that, in R ₈ , ^Ra and R ^b are independently H, -OH, C _1-3 alkyl-O-, a pyranose ring saccharide or a furanose ring saccharide. The compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof, characterized in that, in R ₈ , ^Ra and R ^b are independently H, -OH, methoxy or α-L-arabinopyranosyl. The compound or pharmaceutically acceptable salt or solvate thereof according to claim 14, characterized in that the compound represented by formula (I) is a compound of formula (I-c); In _R8 , ^Ra and ^Rb are each independently H, -OH or methoxy. 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. The compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, characterized in that R ₇ is The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, characterized in that (Ia) In the compound, R ₁ is _R7 is R ₈ is Wherein, R ^c is independently selected from any one of trifluoroacetyl, trichloroacetyl and tribromoacetyl; (Ib) In the compound, _R4 is H, methyl, ethyl or benzyl, and _R8 is ^Ra (Ic) In the compound, R ₁ is _R4 is H, methyl, ethyl or benzyl, _R8 is 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), R ₁ is arabinopyranosyl or rhamnopyranosyl, R ₄ is H or benzyl, _R8 is The compound according to claim 20 or a pharmaceutically acceptable salt or solvate thereof, characterized in that R ₁ is The compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 8, 14 to 19, 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 glycosyl or a furanose ring glycosyl; R ₈ is _R4 is H or benzyl. The compound according to claim 22 or a pharmaceutically acceptable salt or solvate thereof, characterized in that _R1 is arabinopyranosyl or rhamnopyranosyl; R ₈ is _R4 is H or benzyl. The compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 8, 14 to 19, characterized in that the compound represented by formula (I) is a compound of formula (I-c); the compound of formula (I-c) satisfies one, two or three of the following characteristics: _R1 is a pyranose ring group or a furanose ring group; R ₈ is _R4 is H or benzyl. The compound according to claim 24 or a pharmaceutically acceptable salt or solvate thereof, characterized in that _R1 is arabinopyranosyl or rhamnopyranosyl; R ₈ is _R4 is H or benzyl. The compound according to claim 24 or a pharmaceutically acceptable salt or solvate thereof, characterized in that R _{8 R4} is H. 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:


An antibacterial composition, characterized in that it comprises the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof. 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. The use according to claim 29, characterized in that 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: 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. 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. 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. The method according to claim 32 is 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 Streptococcus, beta-hemolytic Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Helicobacter pylori and Mycobacterium abscessus. The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof, for use in treating, improving or preventing bacterial infection or a disease caused by bacterial infection. 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 Enterococcus, linezolid-resistant Enterococcus, 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, and the disease caused by the bacterial infection includes a disease caused by drug-resistant bacterial infection, and optionally, the drug-resistant bacterial infection disease includes infection with methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and linezolid-resistant Enterococcus. Disease caused by at least one of the Enterococci. A product comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof. 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. The product according to claim 36 or the method according to claim 37, wherein the product comprises at least one of medical devices, daily necessities, cosmetics and packaging supplies, and the daily necessities comprise one or more of cleaning supplies, sanitary care supplies, bedding, kitchen utensils, dining utensils and toys. A disinfectant comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof. 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 object in need. Use of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof as a disinfectant. A FtsZ protein inhibitor, comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof. A method for inhibiting FtsZ protein, comprising contacting cells with an effective amount of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt or solvate thereof. Use of the compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof as an FtsZ protein inhibitor.