Star-shaped β-antibacterial glycopeptide, preparation method and application thereof

Abstract

The present application discloses a star-shaped β-antimicrobial glycopeptide, a preparation method and application thereof. The star-shaped β-antimicrobial glycopeptide has a structure shown in the general formula (I): each substituent in the general formula (I) has the same definition as in the specification. The star-shaped β-antimicrobial glycopeptide or its pharmaceutically acceptable salt has good biocompatibility and antibacterial properties, as well as low cytotoxicity, and can be used in combination with different antibiotics to restore and enhance the bactericidal effect of antibiotics.

Description

Technical Field

[0001] The present application specifically relates to a star-shaped β-antimicrobial glycopeptide, a preparation method thereof and its application in medicine, and belongs to the field of medicine. Background Art

[0002] The discovery and application of antibiotics have greatly promoted the development of modern medicine. However, in the past few decades of antibiotic treatment, bacteria inevitably choose escape mutations to develop resistance to antibiotics. Carbapenem antibiotics are currently the last effective antibiotic for difficult-to-treat Gram-negative infections. However, the extensive use of carbapenems in hospitals has promoted the rapid emergence and spread of carbapenem-resistant Gram-negative bacteria. At the same time, despite various efforts to develop new antibiotics, the discovery of new antibiotics has almost stagnated. In the past fifty years, no new type of antibiotic that can kill Gram-negative bacteria has been discovered.

[0003] Among many reasons, the main challenge is that Gram-negative bacteria have a low permeability outer membrane and an efficient efflux pump system. The low permeability outer membrane can prevent drug molecules from entering the internal targets of bacteria, while the efficient efflux pump system can expel antibiotics that enter the internal targets of bacteria out of the bacteria. These two processes greatly limit the concentration accumulation of antibiotics at their drug targets, causing the antibiotics to lose their effectiveness. Carbapenem-resistant Gram-negative bacteria have now been listed by the World Health Organization as a type of bacteria that urgently needs to find new antibiotics or new treatments.

[0004] The discovery of natural antimicrobial peptides has greatly stimulated extensive research on this type of antimicrobial drugs in order to transform them into clinical applications. This is because they have the advantages of rapid broad-spectrum antimicrobial efficacy and low frequency of drug resistance. Although the initial experimental results were exciting, with more than three thousand antimicrobial peptides discovered, there have been limited successful cases of natural antimicrobial peptides from research discovery to clinical application. So far, only five natural antimicrobial peptides have been approved for clinical use, including nisin, gramicidin, polymyxin, daptomycin and bee venom peptide. Among various reasons, the main disadvantages are their cytotoxicity, instability in the body, easy adsorption by proteins and high production costs.

[0005] Compared to natural alpha peptides, beta peptides have an additional methylene group on the main chain. This gives beta peptides greater molecular chain flexibility, allowing the formation of different types of secondary structures to exhibit amphiphilic conformations, which is one of the key factors that contribute to the antimicrobial activity of antimicrobial peptides. Another outstanding feature of beta peptides is their resistance to protease cleavage, which improves in vivo stability. These properties make beta peptides more attractive as candidate antimicrobial agents. However, the antimicrobial properties and biocompatibility of existing beta peptides still need to be further improved. Summary of the invention

[0006] The main purpose of the present application is to provide a star-shaped β-antimicrobial glycopeptide, a preparation method thereof and its application in medicine to overcome the deficiencies of the prior art.

[0007] In order to achieve the aforementioned invention objectives, the technical solutions adopted in this application include:

[0008] The first aspect of the present application provides a compound represented by general formula (I):

[0009]

[0010] Wherein, Core is a structural unit having a cyclic group;

[0011] R1, R2, R3, and R4 are each independently selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alicyclic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro, or hydroxyl;

[0012] n is 0-6, m is 3-100, and x and y are 1-50.

[0013] The second aspect of the present application provides a star-shaped β-antimicrobial glycopeptide, the outer layer of which is a helical glycopeptide block, and the inner layer is a positively charged polydimethylamino beta-lactam block. The structure of the star-shaped β-antimicrobial glycopeptide is shown in general formula (I).

[0014] The third aspect of the present application provides a method for preparing a compound represented by general formula (I), the method comprising:

[0015] (i) according to reaction formula a, a precursor compound containing Core is polymerized with a compound represented by formula (II) and a compound represented by formula (III) to obtain a polymer represented by formula (IV);

[0016]

[0017] (ii) According to reaction formula (b), deprotect the polymer represented by formula (IV)

[0018]

[0019] The fourth aspect of the present application provides a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0020] The fifth aspect of the present application provides the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the pharmaceutical composition as an antibacterial agent.

[0021] The sixth aspect of the present application provides the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for treating or preventing bacterial infection or a disease caused by the bacterial infection.

[0022] The seventh aspect of the present application provides the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the pharmaceutical composition as a cell efflux pump inhibitor and / or a bacterial membrane permeabilizing agent.

[0023] The eighth aspect of the present application provides a method for treating or preventing a bacterial infection or a disease caused by the bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound represented by general formula (I) or the pharmaceutical composition.

[0024] In some embodiments, the bacteria is multi-drug resistant.

[0025] In some embodiments, the method further comprises administering to the subject an effective amount of other antibacterial agents. The other antibacterial agents include, but are not limited to, ampicillin, cloxacillin, oxacillin and piperacillin, cephalosporins such as cefaclor, cefmandol, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime, ceftriaxone and cephalosporins; carbapenems including, for example, imipenem and meropenem; and glycopeptides, macrolides, quinolones, tetracyclines and aminoglycosides. In addition, the other antibacterial agents can also be selected from rifampicin, ciprofloxacin, levofloxacin, piperacillin, co-trimoxazole, gentamicin, lobramycin, erythromycin ethylsuccinate, erythromycin, clarithromycin, neomycin, spiramycin, acetylspiramycin, chloramphenicol, trimethoprim, sulfamethoxazole, carbenicillin, polymyxin B, colistin, amikacin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, doripenem, cilastatin, cefadroxil, cephalothin, cephalexin, cefamandole, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftibuten, cefazolin, cefepime, teicoplanin, vancomycin, roxithromycin , troleandomycin, telithromycin, spectinomycin, amoxicillin, carbenicillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin, ticarcillin, bacitracin, enoxacin, gatifloxacin, moxifloxacin, norfloxacin, trovafloxacin, mafenide, sulfazosulfonamide, sulfacetamide, sulfamethoxazole, sulfa, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, swollenamine, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, bifenthrin suppository, mupirocin, nitrofurantoin, pyrazinamide, quinupristin / dalfopristin, isoflavone, and tinidazole. Any one or more combinations thereof.

[0026] The compound shown in the general formula (I) provided in the present application is a non-natural β-antibacterial glycopeptide, and its chemical structure is a segmented star polymer, the outer layer of which is a helical glycopeptide block, and the inner layer is a positively charged polydimethylamino beta-lactam block. Through this star structure, it can not only increase the permeability of the bacterial outer membrane and destroy the bacterial molecular efflux pump, but also use the outer glycopeptide block to simulate the cell surface polysaccharide molecules to further inhibit bacterial infection, and at the same time, it can further reduce protein adsorption by forming a hydration isolation layer, especially it can better reduce the cytotoxicity caused by positive charge. The compound or its salt can be used in combination with different antibiotics to restore and enhance the bactericidal effect of antibiotics. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0028] Figure 1 The 1H NMR spectrum of a star-shaped β-antimicrobial glycopeptide in Example 1 is shown.

[0029] Figure 2 The gel permeation chromatogram of a star-shaped β-antimicrobial glycopeptide before deprotection in Example 1 is shown.

[0030] Figure 3 The cytotoxicity of a star-shaped β-antimicrobial glycopeptide before deprotection in Example 1 is shown.

[0031] Figure 4 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of rifampicin against carbapenem-resistant Acinetobacter baumannii as shown in Example 1 by the checkerboard broth microdilution assay.

[0032] Figure 5 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of roxithromycin against carbapenem-resistant Acinetobacter baumannii as shown in Example 1 by the checkerboard broth microdilution assay.

[0033] Figure 6 The results of Example 1 show that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of clarithromycin against carbapenem-resistant Acinetobacter baumannii by the checkerboard broth microdilution assay.

[0034] Figure 7 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of erythromycin against carbapenem-resistant Acinetobacter baumannii as shown in Example 1 by the checkerboard broth microdilution assay.

[0035] Figure 8 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of novobiocin against carbapenem-resistant Acinetobacter baumannii as shown in Example 1 by the checkerboard broth microdilution assay.

[0036] Fig. 9 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of spiramycin against carbapenem-resistant Acinetobacter baumannii as shown in Example 1 by the checkerboard broth microdilution assay.

[0037] Fig.10It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of acetylspiramycin against carbapenem-resistant Acinetobacter baumannii as shown in Example 1 by the checkerboard broth microdilution assay.

[0038] Fig.11 It is shown that the time-kill curve measurement in Example 1 shows that the combined use of star-shaped β-antimicrobial glycopeptide and rifampicin has an excellent bactericidal effect on carbapenem-resistant Acinetobacter baumannii.

[0039] Fig.12 It is shown that the time-kill curve measurement in Example 1 shows that the combined use of star-shaped β-antimicrobial glycopeptide and novobiocin has an excellent bactericidal effect on carbapenem-resistant Acinetobacter baumannii.

[0040] Fig.13 It is shown that the time-kill curve measurement in Example 1 shows that the combined use of star-shaped β-antimicrobial glycopeptide and clarithromycin has an excellent bactericidal effect on carbapenem-resistant Acinetobacter baumannii.

[0041] Fig.14 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of novobiocin against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0042] Fig.15 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of erythromycin against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0043] Fig.16 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of clarithromycin against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0044] Fig.17 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of roxithromycin against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0045] Fig.18 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of acetylspiramycin against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0046] Fig.19 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of erythromycin ethylsuccinate against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0047] Fig. 20 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of rifampicin against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay.

[0048] Fig.21 It is shown that the star-shaped β-antimicrobial glycopeptide enhances the bactericidal effect of nalidixic acid against common Acinetobacter baumannii (ATCC19606) as shown in Example 1 by the checkerboard broth microdilution assay. DETAILED DESCRIPTION

[0049] In view of the defects of the prior art, the inventor of this case has proposed the technical solution of this application after long-term research and extensive practice. The technical solution of this application will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of this application, not all of them. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application. It should also be noted that, unless otherwise defined, all technical and scientific terms used in this article have the same meaning as those commonly understood by ordinary technicians in this field.

[0050] Some embodiments of the present application provide a compound represented by general formula (I):

[0051]

[0052] or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt of said compound, or a mixture thereof, in particular a pharmaceutically acceptable salt of said compound;

[0053] Wherein, Core is a structural unit having a cyclic group;

[0054] R1, R2, R3, and R4 are each independently selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alicyclic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro, or hydroxyl;

[0055] n is 0-6, m is 3-100, and x and y are 1-50.

[0056] In some embodiments, the structural unit having a cyclic group includes a substituted or unsubstituted 3-12-membered cycloalkyl group, a substituted or unsubstituted 3-12-membered heterocyclic group, a substituted or unsubstituted 6-10-membered aryl group, or a substituted or unsubstituted 5-10-membered heteroaryl group, an organic macromolecular residue having a cyclic group (e.g., a cyclodextrin molecular residue), or an inorganic compound molecular residue having a cyclic group (e.g., a cage-type polysilsesquioxane molecular residue).

[0057] Furthermore, the structural unit having a cyclic group is selected from substituted or unsubstituted phenyl groups.

[0058] In some specific embodiments, the compound is a compound represented by general formula (I-1):

[0059]

[0060] Wherein, R5 and R6 are selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alicyclic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro or hydroxyl.

[0061] In some embodiments, the aforementioned alkyl group may be linear or branched and may be optionally substituted, for example, it may be selected from methyl, ethyl, 1-propyl or n-propyl, 2-propyl or isopropyl, 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or sec-butyl, 1,1-dimethylethyl or tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl, etc., and is not limited thereto.

[0062] In some embodiments, the aforementioned alkoxy group may be linear or branched, for example, may be selected from but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

[0063] In some embodiments, the aforementioned alkenyl group can be straight or branched, and can be optionally substituted, i.e., substituted or unsubstituted. For example, the aforementioned alkenyl group can be selected from, but not limited to, vinyl, propenyl, butenyl, 1,4-butadienyl, pentenyl, hexenyl, 4-methylhex-1-enyl, 4-ethyl-2-methylhex-1-enyl, etc.

[0064] In some embodiments, the aforementioned alkynyl group may be linear or branched, and may be optionally substituted. For example, the aforementioned alkynyl group may be selected from, but not limited to, ethynyl, propynyl, butynyl, and the like.

[0065] In some embodiments, the aforementioned alicyclic group includes cycloalkyl and cycloalkenyl, for example, can be selected from but not limited to cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane and cycloheptene, etc.

[0066] In some embodiments, the aforementioned aryl group may be a 6-membered carbocyclic aromatic ring such as phenyl, or a 7-12-membered bicyclic ring such as naphthalene, indane, and 1,2,3,4-tetrahydroquinoline, etc., but is not limited thereto.

[0067] In some embodiments, the aforementioned heterocycle is an aliphatic spirocycle containing at least one heteroatom selected from N, O and S, which can be selected from, but not limited to, 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, oxirane, aziridine, azetidinyl, tetrahydropyridinyl, thiomorpholinyl, thienyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl, thienyl, 1,4-oxacycloalkyl, 1,4-dioxacycloalkyl Heptane, 1,4-oxacycloheptane, 4-oxacycloheptane, 4-oxacycloheptane, 1-oxacycloheptane, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, 2-pyranyl, tetrahydrothiophenyl 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, 1,4-dioxane, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithiophenyl, dithiophenyl, pyrazolidinyl imidazolinyl, pyrimidinyl nonyl, 1,1-dioxo-thiodihydropyridinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, etc., and are not limited thereto.

[0068] In some embodiments, the aforementioned alkylheterocycle refers to a chemical substituent comprising an alkyl group coupled to a heterocycle or a substituted heterocycle.

[0069] In some embodiments, the aforementioned heteroaryl refers to an aromatic heterocycle, which can be formed by five, six, seven, eight, nine or more atoms. The heteroaryl can be optionally substituted. For example, it can be selected from but not limited to an aromatic C5-C15 heterocyclic group containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substitutions and benzo and pyrido fused derivatives.

[0070] Preferably, R1, R2, and R3 are each independently selected from a C1-C6 alkyl group, a hydroxyl group, or an amine group.

[0071] In some cases, R3 may also be selected from amine, hydroxyl, and the like.

[0072] Preferably, R4, R5 and R6 are hydrogen atoms.

[0073] In a more specific implementation case, the compound is a compound represented by the following formula:

[0074]

[0075] Some embodiments of the present application also provide a star-shaped β-antimicrobial glycopeptide, whose outer layer is a helical glycopeptide block and whose inner layer is a positively charged polydimethylamino beta-lactam block. The structure of the star-shaped β-antimicrobial glycopeptide is shown in general formula (I).

[0076] The sources of the glycopeptide blocks include monosaccharides such as glucose, galactose, mannose, altrose, glucosamine, galactose amino, mannose amino or disaccharide maltose, but are not limited thereto.

[0077] The star-shaped β-antimicrobial glycopeptide provided in the embodiments of the present application is a type of star-shaped block polymer, the outer helical glycopeptide of which can be better exposed in the outer layer of the compound, thereby binding to sugar receptors on the surface of bacteria to prevent infection; forming a hydration layer to prevent protein adsorption; and blocking the binding of the cationic block in the inner layer to mammalian cells, thereby further improving biocompatibility.

[0078] Some embodiments of the present application also provide a method for preparing a compound represented by general formula (I), the method comprising:

[0079] (i) according to reaction formula a, a precursor compound containing Core is polymerized with a compound represented by formula (II) and a compound represented by formula (III) to obtain a polymer represented by formula (IV);

[0080]

[0081] (ii) According to reaction formula (b), deprotect the polymer represented by formula (IV)

[0082]

[0083] Among them, the compound with a protective group shown in formula (II) and the compound with a protective group shown in formula (III) can be synthesized in a manner known in the art. For example, glucose-derived beta-lactam (AS(Bn)) can be synthesized according to the document (J.Am.Chem.Soc.134, 16255-16264 (2012)). And, carboxybenzyl (Cbz)-protected beta-lactam with an amine group (DM(Cbz)) can be synthesized according to the document (Angew.Chem.Int.Ed.2020doi.org / 10.1002 / anie.201914304).

[0084] Wherein, the definition of "protecting group" is well known in the art, generally refers to a chemical group that reacts and binds to a functional group in a molecule to prevent the functional group from participating in subsequent reactions of the molecule, but the group can be subsequently removed to regenerate the unprotected functional group. In the present application, the protecting group includes but is not limited to benzyl, carboxybenzyl (Cbz), tert-butoxycarbonyl (Boc), etc., preferably carboxybenzyl.

[0085] Furthermore, step (a) comprises: preparing the protective polymer in the presence of lithium bis(trimethylsilyl)amide and 4-tert-butylbenzoyl chloride.

[0086] Furthermore, the reaction temperature used in step (a) can be 0°C to 66°C, preferably room temperature.

[0087] Furthermore, step (b) comprises: deprotecting the protected polymer under the conditions of sodium and liquid ammonia.

[0088] Furthermore, the reaction temperature used in step (b) can be -80°C to -50°C, preferably -78°C to -55°C.

[0089] Some embodiments of the present application also provide a pharmaceutical composition comprising the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0090] In this specification, the definition of pharmaceutically acceptable salts is well known in the art, that is, those salts suitable for contact with human tissues and organs and tissues and organs of lower animals within the appropriate pharmaceutical evaluation range, without excessive toxicity, irritation, allergic reaction or similar reaction. The salt can be any salt, organic or inorganic addition salt, especially any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy, such as salts formed by the reaction of the compound represented by general formula (I) with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid or with organic acids such as formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid.

[0091] In some preferred embodiments, the pharmaceutical composition further comprises other antibacterial agents.

[0092] Further, the other antibacterial agents include but are not limited to ampicillin, cloxacillin, oxacillin and piperacillin, cephalosporins such as cefaclor, cefmandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime, ceftriaxone and cephalosporins; carbapenems including, for example, imipenem and meropenem; and glycopeptides, macrolides, quinolones, tetracyclines and aminoglycosides. In addition, the other antibacterial agents can also be selected from rifampicin, ciprofloxacin, levofloxacin, piperacillin, co-trimoxazole, gentamicin, lobramycin, erythromycin ethylsuccinate, erythromycin, clarithromycin, neomycin, spiramycin, acetylspiramycin, chloramphenicol, trimethoprim, sulfamethoxazole, carbenicillin, polymyxin B, colistin, amikacin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, doripenem, cilastatin, cefadroxil, cephalothin, cephalexin, cefamandole, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftibuten, cefazolin, cefepime, teicoplanin, vancomycin, roxithromycin , troleandomycin, telithromycin, spectinomycin, amoxicillin, carbenicillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin, ticarcillin, bacitracin, enoxacin, gatifloxacin, moxifloxacin, norfloxacin, trovafloxacin, mafenide, sulfazosulfonamide, sulfacetamide, sulfamethoxazole, sulfa, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, swollenamine, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, bifenthrin suppository, mupirocin, nitrofurantoin, pyrazinamide, quinupristin / dalfopristin, isoflavone, and tinidazole. Any one or more combinations thereof.

[0093] Wherein, the other antibacterial agents include but are not limited to anti-Gram-positive antibiotics, and the antibacterial range of the antibacterial agent includes Gram-negative bacteria. Further, the antibacterial range of the anti-Gram-positive antibiotics can be expanded by using the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, so that it is also effective against Gram-negative bacteria.

[0094] In the present specification, the aforementioned pharmaceutically acceptable carrier includes pharmaceutically acceptable materials, compositions, excipients, etc., such as liquid or solid fillers, diluents, excipients or solvent encapsulating materials, specifically including but not limited to the following substances: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; sterile distilled water; ethanol; pH buffer solution; polyester, polycarbonate or polyanhydride; and the like.

[0095] In some embodiments, in order to prepare the pharmaceutical composition, a pharmaceutically inert inorganic or organic excipient may be used. For example, in order to prepare pills, powders, gelatin capsules or suppositories, lactose, talcum powder, stearic acid and its salts, fats, waxes, solid or liquid polyols, natural oils and hardened oils, etc. may be used as pharmaceutically acceptable carriers. In order to prepare injections, oral solutions, sprays, aerosol preparations, powders, etc., water, alcohol, glycerol, polyols and suitable mixtures thereof, and vegetable oils, etc. may be used as pharmaceutically acceptable carriers. Further, after the aforementioned preparations are prepared, the preparations may be sterilized in a variety of ways, including filtering through a bacterial retention filter, or by adding a sterilizing agent in the form of a sterile solid composition.

[0096] Some embodiments of the present application also provide the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the pharmaceutical composition as an antibacterial agent.

[0097] In this specification, the "antimicrobial agent" refers to any substance or combination thereof that can: (i) inhibit, reduce or prevent bacterial growth; (ii) have the ability to inhibit or reduce the ability of bacteria to cause infection in a subject; (iii) have the ability to inhibit or reduce the ability of bacteria to reproduce or remain infectious in the environment.

[0098] Some embodiments of the present application also provide the use of the compound represented by the general formula (I) or its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for treating or preventing bacterial infection or a disease caused by the bacterial infection.

[0099] Wherein, the bacteria include at least one of multi-drug resistant bacteria and sensitive bacteria.

[0100] Furthermore, the bacteria have multi-drug resistance, that is, the bacteria are resistant to multiple drugs of different chemical structures and / or are resistant to drugs targeting different targets.

[0101] In the present specification, the bacteria include Gram-negative bacteria (such as Escherichia coli, Pseudomonas aeruginosa, Helicobacter pylori, Klebsiella pneumoniae, etc.), Gram-positive bacteria, etc., especially carbapenem-resistant Gram-negative bacteria, such as carbapenem-resistant Acinetobacter baumannii.

[0102] In this specification, the drug can be a preparation in various forms and can be used in various ways such as oral administration, injection, external application, embolization, aerosol, etc. The preparation form suitable for oral administration can be tablets, lozenges, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, etc. In addition, the drug can also contain sweeteners, flavoring agents, colorants, preservatives, antioxidants. The preparation form suitable for injection can be a sterile injection aqueous solution form or an oil suspension form, wherein the solvent used includes but is not limited to water, Ringer's solution, sodium chloride solution, glucose solution, etc. The preparation form suitable for suppositories is solid at normal temperature but liquid in the rectum, and the drug carrier therein can dissolve in the rectum to release the drug and is non-irritating to the rectum.

[0103] Some embodiments of the present application also provide the use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or the pharmaceutical composition as a cell efflux pump inhibitor and / or a bacterial membrane permeabilizing agent.

[0104] The definitions of the cell efflux pump inhibitor and / or bacterial membrane permeabilizing agent are well known in the art. Specifically, the cell efflux pump refers to a protein assembly that exports substrate molecules from the cytoplasm or periplasm of a cell in an energy-dependent manner. The bacterial membrane permeabilizing agent refers to any compound that can reduce the integrity of the bacterial cytoplasmic membrane or destroy the bacterial cytoplasmic membrane.

[0105] Some embodiments of the present application also provide a method for treating or preventing a bacterial infection or a disease caused by the bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound represented by general formula (I) or the pharmaceutical composition.

[0106] In some embodiments, the bacteria is multi-drug resistant.

[0107] In some embodiments, the method further comprises administering to the subject an effective amount of another antibacterial agent. The other antibacterial agent is as described above and will not be described in detail herein. Furthermore, a person skilled in the art can determine the optimal dosage ratio of the compound represented by general formula (I) and the other antibacterial agent in a manner known in the art.

[0108] It should be noted that the compound represented by the general formula (I) can be administered to a subject in need thereof alone or in combination with one or more other antibacterial agents (simultaneously, sequentially or separately) in an effective amount.

[0109] In the present specification, the subject may be any human or non-human animal, preferably a mammal, and more preferably a human.

[0110] Since the compound represented by the general formula (I) and the other antibacterial agents have a synergistic effect when used in combination, the therapeutically effective dose of the compound represented by the general formula (I) and / or other antibacterial agents when used alone can be lower than their standard doses. For example, the therapeutically effective dose can be 1% to 99%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, 5% to 20%, 1% to 10%, 0.1% to 1%, 0.01% to 1%, 0.001% to 1%, etc. of the standard dose.

[0111] The technical solution of the present application is further described in detail below in conjunction with several preferred embodiments and drawings. This embodiment is implemented on the premise of the technical solution of the invention, and a detailed implementation method and specific operation process are given, but the protection scope of the present application is not limited to the following embodiments.

[0112] Example 1 The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0113]

[0114] A method for synthesizing the star-shaped β-antimicrobial glycopeptide comprises the following steps:

[0115] (1) Preparation of beta-lactam monomer

[0116] Glucose-derived beta-lactam (AS(Bn)) was synthesized according to the literature (J. Am. Chem. Soc. 134, 16255-16264 (2012)). Carboxybenzyl (Cbz)-protected amine-containing beta-lactam (DM(Cbz)) was synthesized according to the literature (Angew. Chem. Int. Ed. 2020 doi.org / 10.1002 / anie.201914304).

[0117] (2) General procedure of polymerization

[0118] The entire polymerization process was carried out in an inert gas-protected glove box. First, 0.4M DM(Cbz) and AS(Bn), 0.02M 1,3,5-benzenetricarboxyl chloride and 0.15M lithium bis(trimethylsilyl)amide (LiHMDS) were prepared in anhydrous tetrahydrofuran. Then, 1ml of 1,3,5-benzenetricarboxyl chloride and 900μl of DM(Cbz) were added to a 10ml oven-dried round-bottom flask and mixed. The solution was mixed evenly at 30°C for 3min. Subsequently, 1ml of LiHMDS solution was injected into the reaction flask to initiate polymerization. After reacting for a period of time at room temperature, after confirming that the DM(Cbz) monomer was completely consumed by TLC, 450μl of AS(Bn) solution was added to the reaction mixture to continue the reaction until the monomer was completely consumed, and then the reaction was quenched with a few drops of methanol. The polymer was purified by repeated dissolution in dichloromethane (3 cycles) and precipitation in hexane.

[0119] (3) Polymer deprotection

[0120] 140 mg of protected polymer and 54 mg of potassium tert-butoxide (KOt-Bu) were dissolved in 5.0 ml of anhydrous THF. The polymer solution was added dropwise to a rapidly stirred solution of sodium (120 mg) in liquid ammonia (~15 ml) at -78°C and under nitrogen. The sodium was washed in anhydrous toluene and hexane and cut into small pieces before addition. The reaction was reacted at -78°C for 4 hours, and then saturated ammonium chloride was added dropwise to quench the reaction until the blue color disappeared. The remaining ammonia was evaporated at room temperature overnight. The filtered solution was washed with deionized water and dialyzed with a 1000 Da cut-off dialysis bag for 2 days, changing the water every 2 to 3 hours. Finally, a white solid sample was obtained by freeze drying.

[0121] This example successfully synthesized the star-shaped β-antibacterial glycopeptide through anionic ring-opening polymerization, which is a segmented star-shaped β-polypeptide. The outer layer of the segmented star-shaped β-polypeptide is a helical glycopeptide block, which can improve biocompatibility, prevent protein adsorption and prevent infection, and the inner layer is a positively charged polydimethylamino beta-lactam block, which increases the permeability of the bacterial outer membrane and destroys the bacterial molecular efflux pump. Figure 1 As shown, the molecular structure of the polypeptide was confirmed by H NMR, and the integral ratio of the outer glycopeptide block and the inner positively charged polydimethylamino beta-lactam block was 1:2, which was consistent with the monomer feed ratio. Figure 2 The molecular weight of the polypeptide is 26 as measured by gel permeation chromatography (GPC), which is close to the monomer / initiator feed ratio of 27:1 and has a relatively narrow molecular weight distribution. .

[0122] Carbapenem-resistant Acinetobacter baumannii is the first on the list of "superbugs" published by the World Health Organization (WHO) that are the most resistant and most threatening to human health. Table 1 is a table of drug resistance of carbapenem-resistant Acinetobacter baumannii (DR-AB), which shows that it has developed resistance to almost all antibiotics commonly used in clinical practice.

[0123] In this example, the activity of the star-shaped β-antimicrobial glycopeptide was tested using the bacteria, and the testing method included:

[0124] 1. Minimum inhibitory concentration (MIC) value detection

[0125] 1) Activation: streak a single colony from the LB plate and add it to a centrifuge tube containing 5 ml of MHB medium. Place it in a shaker at 37°C, 175 rpm, and culture overnight.

[0126] 2) Re-cultivation: Pipette 50 μl of activated bacterial solution into a centrifuge tube containing 5 ml of MHB culture medium and culture with shaking for 3-4 hours.

[0127] 3) Prepare antibiotic solution (10 mg / ml).

[0128] 4) Add 50 μL of MHB to each well of rows B to F of the 96-well plate, and then pipette 50 μL of MHB into wells B1, C1, D1, E1, and F1 respectively.

[0129] 5) Pipette 10.24 μL of MHB from each of wells B1, C1, D1, E1, and F1 and discard.

[0130] 6) Pipette 10.24 μL of antibiotic solution respectively, add to wells B1, C1, D1, E1, and F1, and mix well.

[0131] 7) Pipette 50 μL of the mixture from the first column (B2-F1) to the second column (B2-F2) and pipette to mix. Repeat this process until the last column (B12-F12).

[0132] 8) Pipette 50 μL of the mixture from the last column of wells (B12-F12) and discard.

[0133] 9) Remove the re-cultured bacteria from the shaker.

[0134] 10) dilute the bacterial suspension and use a microplate reader to measure the OD value until the bacterial suspension is diluted to OD≈0.2 (at this time, the bacterial suspension is about 10 9 CFU / ml). Then dilute the bacterial suspension 1000 times to get 10 6 CFU / ml bacterial suspension.

[0135] 11) Pipette 50 μL of 106 CFU / ml bacterial suspension into the first five rows of wells (B2-F12).

[0136] 12) Pipette the bacterial suspension and MHB to complete the positive and negative controls in the 6th row of wells (G2-G12) (6 positive controls such as G2-G6: 100 μL MHB; 6 negative controls such as G7-G12: 50 μL MHB + 50 μL bacterial suspension).

[0137] 13) Oscillate the 96-well plate for 3-4 minutes, seal it and place it in a biochemical incubator at 37°C for 16-18 hours.

[0138] 14) Remove the 96-well plate from the incubator, visually inspect the turbidity to determine the MIC value, then use a microplate reader to measure the 595 nm OD value and record it, export the data and make a judgment based on the breakpoint interpretation.

[0139] 2. Chessboard dilution method to measure the effect of combined medication

[0140] 1) Activate and re-cultivate the bacteria and prepare the antibiotic solution (same as steps 1)-3) of the MIC experiment).

[0141] 2) Use a deep-well plate to horizontally arrange a 2-fold gradient concentration solution of the antibiotic (starting from 16×MIC, with MHB in the last well).

[0142] 3) Use a deep-well plate to vertically arrange a 2-fold gradient concentration solution of the sample (starting from 4×256 μg / ml, with MHB in the last well).

[0143] 4) Use a multichannel pipette to draw 25 μL of the antibiotic gradient concentration solution and sample gradient concentration solution from the deep-well plate, and fill the entire 96-well plate by row and column.

[0144] 5) Add 50 μL of 106 CFU / ml bacterial suspension to each well (the preparation method is the same as step 10) of the MIC experiment).

[0145] 6) Seal, shake, incubate and read (same as MIC test steps 13)-14)).

[0146] The above activity tests show that the effects that can be achieved by using the star-shaped β-antimicrobial glycopeptide of this embodiment in combination with a variety of antibiotic adjuvants include but are not limited to:

[0147] (1) Increasing the bactericidal range of antibiotics can make antibiotics that are only effective against Gram-positive bacteria (such as rifampicin) also effective against Gram-negative bacteria. Figure 3 ;

[0148] (2) Greatly enhance the bactericidal effect of antibiotics and reduce the minimum bactericidal concentration of multiple antibiotics by 16-256 times, see Figure 4-Figure 9 ;

[0149] (3) Reduce the possibility of bacterial resistance because two molecules act on different locations at the same time, making it difficult for bacteria to make targeted mutations at the same time.

[0150] Some experimental results of the star-shaped β-antimicrobial glycopeptide in Example 1 that enhance the bactericidal effect of other antibiotics on carbapenem-resistant Acinetobacter baumannii can also be found in Figure 4-Figure 13 For bactericidal effects against common Acinetobacter baumannii, see Figure 14-Figure 21 .

[0151] Example 2: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0152]

[0153] The structure of Core is the same as that of Core in the star-shaped β-antimicrobial glycopeptide of Example 1. Compared with Example 1, the 1H NMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.02-4.39 (3H), 3.65 (2H, br), 3.37-2.96 (9H), 1.37 (6H, br). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, but the beta-lactam monomer used is a monomethyl-substituted beta-lactam, and its synthesis method refers to (J.Am.Chem.Soc.2007, 129, 15474-15476), and the other steps and raw materials are basically the same as those of Example 1.

[0154] Example 3: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0155]

[0156] The structure of Core is the same as that of Core in the star-shaped β-antimicrobial glycopeptide of Example 1. Compared with Example 1, the 1HNMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.02 (2H), 3.65-2.75 (13H). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, but the beta-lactam monomer used is a beta-lactam without methyl substitution, and its synthesis method refers to (J.Am.Chem.Soc.2014, 136, 4333-4342), and the other steps and raw materials are basically the same as Example 1.

[0157] Example 4: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0158]

[0159] The structure of Core is the same as that of Core in the star-shaped β-antimicrobial glycopeptide of Example 1. Compared with Example 1, the 1HNMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.53 (2H, br) 4.02 (1H, br), 3.65 (2H, br), 3.37-2.58 (8H). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, but the beta-lactam monomer used is a single-substituted beta-lactam, and the Cbz-protected methyleneamine group is changed from the α position to the β position of the beta-lactam. The synthesis method thereof refers to (J.Am.Chem.Soc.2013, 135, 5270-5273), and the other steps and raw materials are basically the same as those of Example 1.

[0160] Example 5: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0161]

[0162] Among them, the structure of Core is the same as that of the Core in the star-shaped β-antimicrobial glycopeptide in Example 1. Compared with Example 1, the 1H NMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.32 (3H), 4.02 (2H), 3.65 (2H, br), 3.37-3.0 (5H). 2.50 (4H, br), 1.8-1.3 (12H). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, but the beta-lactam monomer used is a beta-lactam with no methyl substitution and a Cbz-protected methyleneamine carbon chain length increased to 4. The synthesis method thereof refers to (Nat. Commun. 2019, 10, 1-14), and the other steps and raw materials are basically the same as Example 1.

[0163] Example 6: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0164]

[0165] Wherein, the structure of Core is the same as that of Core in the star-shaped β-antimicrobial glycopeptide of Example 1. Compared with Example 1, the 1H NMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.60-4.14 (1H), 4.12-3.52 (4H, br, m), 3.20-2.58 (7H, br, m), 1.37 (12H, br, m). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, but the beta lactam monomer used is changed from glucose to altrolactam monomer, and the synthesis method thereof refers to (J.Am.Chem.Soc.2017, 139, 14217-14223), and the other steps and raw materials are basically the same as those in Example 1.

[0166] Example 7: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0167]

[0168] Wherein, the structure of Core is the same as that of Core in the star-shaped β-antimicrobial glycopeptide of Example 1. Compared with Example 1, the 1H NMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.82 (1H, br), 4.37-4.14 (1H), 4.12-3.52 (4H, br, m), 3.85-2.58 (11H, br, m), 1.37 (12H, br, m). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, but the beta lactam monomer used therein is changed from glucose to galactosyl lactam monomer, and the synthesis method thereof refers to (J.Am.Chem.Soc.2016, 138, 6532-6540), and the other steps and raw materials are basically the same as those in Example 1.

[0169] Example 8: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0170]

[0171] Wherein, Core is 1,2,3,4-cyclobutane tetracarbonyl. Compared with Example 1, the 1HNMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.04 (1H), 3.77-3.53 (2H, br), 3.48-2.69 (9H, br, m), 3.20-2.58, 1.37 (12H, br). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, except that: in step (2), 1,2,3,4-cyclobutane tetrachloride is used to replace 1,3,5-benzenetricarboxylic acid chloride, and the other steps and raw materials are basically the same as Example 1.

[0172] Example 9: The structural formula of a star-shaped β-antimicrobial glycopeptide provided in this example is as follows:

[0173]

[0174] Wherein, Core is 1,2,3,4,5,6-cyclohexane hexacarbonyl. Compared with Example 1, the 1H NMR characterization spectrum of the star-shaped β-antimicrobial glycopeptide includes: δ5.66 (1H, br), 4.04 (1H), 3.77-3.53 (2H, br), 3.48-2.69 (9H, br, m), 3.20-2.58, 1.37 (12H, br). The synthesis method of the star-shaped β-antimicrobial glycopeptide can refer to Example 1, except that: in step (2), 1,2,3,4,5,6-cyclohexane hexachloride is used to replace 1,3,5-benzenetricarboxylic acid chloride, and the other steps and raw materials are basically the same as Example 1.

[0175] Referring to the method of Example 1, the activity of the star-shaped β-antimicrobial glycopeptides provided in Examples 2 to 9 was tested using carbapenem-resistant Acinetobacter baumannii in this example. The results showed that these star-shaped β-antimicrobial glycopeptides were used in combination with a variety of antibiotic adjuvants, which can also increase the bactericidal range of antibiotics, enhance the bactericidal effect of antibiotics, and reduce the possibility of bacterial resistance, and the effect is close to that of the antimicrobial glycopeptides in Example 1.

[0176] In addition, the applicant also prepared other star-shaped β-antimicrobial glycopeptides described in the specification of this application with reference to the aforementioned Examples 1-9, and also tested their antibacterial properties, etc. The results showed that these star-shaped β-antimicrobial glycopeptides were used in combination with a variety of antibiotic adjuvants, and the effects in increasing the bactericidal range of antibiotics, enhancing the bactericidal effect of antibiotics, and reducing the possibility of bacterial resistance were far superior to the existing sugar-derived cationic block poly (β-peptide), β-peptide sugar copolymers, etc.

[0177] It should be understood that the technical solution of the present application is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present application without departing from the purpose of the present application and the scope of protection of the claims shall fall within the scope of protection of the present application.

[0178] Table 1 Drug resistance of carbapenem-resistant Acinetobacter baumannii (CR-AB)

[0179] antibiotic MIC (μg / ml) Drug resistance Ciprofloxacin ＞＝4 Drug resistance Ampicillin\Sulbactam ＞＝32 Drug resistance Levofloxacin ＞＝8 Drug resistance Piperacillin ＞＝128 Drug resistance Co-trimoxazole ＞＝320 Drug resistance Gentamycin ＞＝16 Drug resistance Cefoperazone\Sulbactam 8 Drug resistance Ceftazidime ＞＝64 Drug resistance Ceftriaxone ＞＝64 Drug resistance Cefepime ＞＝64 Drug resistance Piperacillin / Tazobactam ＞＝128 Drug resistance Meropenem ＞＝16 Drug resistance Lobramycin ＞＝16 Drug resistance Imipenem ＞＝16 Drug resistance

Claims

1. A compound represented by general formula (I): Formula (I) in, Core is a structural unit having a cyclic group; R1, R2, R3, and R4 are each independently selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alicyclic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro, or hydroxyl; n is 0~6, m is 3~100, x and y are 1~50.

2. The compound represented by the general formula (I) according to claim 1, characterized in that: The structural unit having a cyclic group includes a substituted or unsubstituted 3- to 12-membered cycloalkyl group, a substituted or unsubstituted 3- to 12-membered heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group or a substituted or unsubstituted 5- to 10-membered heteroaryl group, an organic macromolecular residue having a cyclic group, or an inorganic compound molecular residue having a cyclic group.

3. The compound represented by the general formula (I) according to claim 2, characterized in that: The organic macromolecular residue having a cyclic group includes a cyclodextrin molecular residue.

4. The compound represented by the general formula (I) according to claim 2, characterized in that: The inorganic compound molecular residue having a cyclic group includes a cage-type polysilsesquioxane molecular residue.

5. The compound represented by the general formula (I) according to claim 2, characterized in that: The structural unit having a cyclic group is selected from substituted or unsubstituted phenyl groups.

6. The compound represented by the general formula (I) according to claim 1, characterized in that: The compound is a compound represented by the following formula: 。 7. A stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt of the compound represented by general formula (I) as claimed in any one of claims 1 to 6.

8. A star-shaped β-antimicrobial glycopeptide, characterized in that: The outer layer of the star-shaped β-antimicrobial glycopeptide is a helical glycopeptide block, the inner layer is a positively charged polydimethylamino beta-lactam block, and the structure of the star-shaped β-antimicrobial glycopeptide is shown in general formula (I): Formula (I) Wherein, Core is a structural unit having a cyclic group; R1, R2, R3, and R4 are each independently selected from H, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alicyclic, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C7-C30 alkyl-aryl, substituted or unsubstituted C3-C20 heterocycle, substituted or unsubstituted C4-C30 alkyl-heterocycle, substituted or unsubstituted C5-C15 heteroaryl, C1-C20 hydroxyalkyl, cyano, amino, guanidino, nitro, or hydroxyl; n is 0~6, m is 3~100, x and y are 1~50.

9. The star-shaped β-antimicrobial glycopeptide according to claim 8, characterized in that The sources of the glycopeptide blocks include monosaccharides such as glucose, galactose, mannose, altrose, aminoglucose, aminogalactose, aminomannose or disaccharide maltose.

10. A method for preparing the compound represented by general formula (I) according to claim 1, characterized in that: The method comprises: (i) according to reaction formula a, a precursor compound containing the core is polymerized with a compound represented by formula (II) and a compound represented by formula (III) to obtain a polymer represented by formula (IV); Reaction formula a (ii) According to reaction formula (b), deprotect the polymer represented by formula (IV) Reaction equation b.

11. The method according to claim 10, characterized in that Step (a) comprises: preparing the protected polymer in the presence of lithium bis(trimethylsilyl)amide.

12. The method according to claim 10, characterized in that Step (b) comprises: deprotecting the protected polymer under the conditions of sodium and liquid ammonia.

13. A pharmaceutical composition, characterized in that Include: The compound represented by general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, Or, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9; and A pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, characterized in that: The pharmaceutical composition may also contain other antibacterial agents.

15. The pharmaceutical composition according to claim 14, characterized in that: The other antibacterial agents include ampicillin, cloxacillin, oxacillin, piperacillin, cephalosporins, carbapenems, glycopeptides, macrolides, quinolones, tetracyclines, aminoglycosides, rifampicin, ciprofloxacin, levofloxacin, piperacillin, co-trimoxazole, gentamicin, lobramycin, erythromycin ethylsuccinate, erythromycin, clarithromycin, neomycin, spiramycin, acetylspiramycin, chloramphenicol, trimethoprim, sulfamethoxazole, carbenicillin, polymyxin B, colistin, amikacin, kanamycin, neomycin, Netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, doripenem, cilastatin, cefadroxil, cephalothin, cephalexin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftibuten, cefazolin, cefepime, teicoplanin, vancomycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, amoxicillin, carbenicillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, penicillin, ticarcillin, bacitracin, etoposide Any one or more combinations of norfloxacin, gatifloxacin, moxifloxacin, norfloxacin, trovafloxacin, mafenide, sulfazosulfonamide, sulfacetamide, sulfamethoxazole, sulfonamide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metoprolol suppository, mupirocin, nitrofurantoin, pyrazinamide, quinupristin / dalfopristin, isoflavone, and tinidazole.

16. The pharmaceutical composition according to claim 15, characterized in that: The cephalosporin includes any one or more combinations of cefaclor, cefmandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime and ceftriaxone.

17. The pharmaceutical composition according to claim 15, characterized in that: The carbapenems include any one or more combinations of imipenem and meropenem.

18. Use of the compound represented by general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 13 to 17 as an antibacterial agent.

19. The use according to claim 18, characterized in that: The other antibacterial agents contained in the pharmaceutical composition include antibiotics against Gram-positive bacteria, and the antibacterial range of the antibacterial agent includes Gram-negative bacteria.

20. Use of the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9, or the pharmaceutical composition according to any one of claims 13 to 17 in the preparation of a medicament for treating or preventing bacterial infection or a disease caused by the bacterial infection.

21. The use according to claim 20, characterized in that: The bacteria include at least one of multi-drug resistant bacteria and sensitive bacteria.

22. Use of the compound of general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9, or the pharmaceutical composition according to any one of claims 13 to 17 as a cellular efflux pump inhibitor.

23. Use of the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, the star-shaped β-antimicrobial glycopeptide according to any one of claims 8 to 9, or the pharmaceutical composition according to any one of claims 13 to 17 as a bacterial membrane permeabilizing agent.

Images