3-(2-thiazole-5-ylmethyl) benzoxazolone derivative and application thereof

Abstract

The invention belongs to the field of pharmaceutical compounds, and discloses a 3-(2-thiazole-5-yl methyl) benzoxazolone derivative and application thereof, and the 3-(2-thiazole-5-yl methyl) benzoxazolone derivative has a chemical structure as shown in a general formula A; ; wherein R1 is selected from alkyl with the C atom number of 1-10, naphthenic base with the C atom number of 3-8, substituted or unsubstituted aryl containing 5-10 main chain atoms, aryl heterobase or alkyl with the C atom number of 1-10, cycloalkyl with the C atom number of 3-8, substituted or unsubstituted aryl containing 5-10 main chain atoms and aryl heterobase; in the formula, n is 0-4, and Z is selected from three-to-eight-membered cycloalkyl, three-to-eight-membered heteroalkyl or substituted or unsubstituted aryl and heteroaryl containing 5-10 main chain atoms. The derivative has the effect of inhibiting quorum sensing of pseudomonas aeruginosa, can be used as a novel biological membrane inhibitor, and can also be used as an antibacterial sensitizer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compounds and relates to 3-(2-thiazol-5-ylmethyl)benzoxazolone derivatives and their applications. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] In recent years, antimicrobial resistance has become a major threat to global public health, with the number of deaths caused by drug-resistant bacteria exceeding ten million annually. Antibiotic overuse has exacerbated this crisis, particularly by *Pseudomonas aeruginosa* (…). Pseudomonas aeruginosa Nosocomial infections caused by Gram-negative bacteria, such as α, are particularly challenging, and their multidrug resistance characteristics pose a serious challenge to clinical treatment.

[0004] These pathogens evade drug action through multiple mechanisms, with the quorum sensing (QS) system playing a central role in regulating virulence factor expression, biofilm formation, and the acquisition of drug resistance. Biofilms, as structured bacterial communities encapsulated by extracellular polymers, significantly enhance bacterial resistance to antimicrobial drugs and host immunity, with resistance levels reaching up to 1000 times that of planktonic bacteria, making them a key factor leading to chronic infections and treatment failure. By regulating the expression of virulence factors (such as proteases and exotoxins) through the quorum sensing system, they enhance their invasiveness to host tissues, potentially causing serious infections such as sepsis and peritonitis, especially threatening the lives of immunocompromised patients (such as postoperative or ICU patients). As opportunistic pathogens, they easily colonize the healthcare environment and spread through medical devices and procedures, leading to hospital-acquired infection outbreaks, increasing the healthcare burden and patient mortality.

[0005] The Quantitative Stimulus (QS) system, acting as a "communication mechanism" for bacteria to sense population density and coordinate group behavior, is directly related to their pathogenicity and environmental adaptability. Unlike the bactericidal strategies of traditional antibiotics, QS inhibitors, by interfering with pathogenic pathways rather than directly killing bacteria, can significantly reduce the production of virulence factors and biofilm formation, thereby restoring host immune clearance efficiency and the bactericidal activity of existing antibiotics. Because they do not exert growth selection pressure, these inhibitors are less likely to induce drug-resistant mutations and are considered a highly promising new strategy against drug resistance. Currently, the development of novel inhibitors targeting the QS system has become an important direction for overcoming bacterial resistance, especially for addressing infections caused by multidrug-resistant bacteria such as *Pseudomonas aeruginosa*. Therefore, developing QS inhibitors that can effectively inhibit biofilm formation or reduce bacterial virulence to restore the efficacy of existing antibiotics and delay the evolution of drug resistance has become an urgent need in anti-infective drug research. Summary of the Invention

[0006] The purpose of this invention is to synthesize novel quorum sensing inhibitors for the treatment of diseases caused by drug-resistant Gram-negative bacteria such as *Pseudomonas aeruginosa*. To this end, this invention provides 3-(2-thiazol-5-ylmethyl)benzoxazolone derivatives and their application in the preparation of bacterial quorum sensing inhibitors. These derivatives have structures completely different from previously reported biofilm inhibitors and possess different physicochemical properties. Experiments have shown that these derivatives exhibit inhibitory activity against *Pseudomonas aeruginosa* quorum sensing and can serve as novel biofilm inhibitors and antibacterial sensitizers.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: In a first aspect, the present invention provides a 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative having the chemical structure shown in general formula A; ; Among them, R 1 Selected from alkyl groups having 1 to 10 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, substituted or unsubstituted aryl groups containing 5 to 10 main chain atoms, or aromatic heteroyl groups. ; In this context, n is 0 to 4, and Z is selected from three to eight-membered cycloalkyl, three to eight-membered cyclohexaalkyl, or substituted or unsubstituted aryl and aromatic heteroalkyl containing 5 to 10 main chain atoms; R 1 The substituted aryl or substituted aromatic heterol groups in Z are monosubstituted or polysubstituted by any of the following substituents: alkyl with 1-9 carbon atoms, heteroalkyl with 1-9 carbon atoms, halogen, cyano, nitro, amino, substituted alkyl, substituted alkoxy and substituted amino; Y1, Y2, Y3, Y4, and Y5 are independently selected from N, CH, and C(R), respectively. 2 ), R 2 Selected from alkyl groups having 1 to 3 carbon atoms, heteroalkyl groups having 1 to 3 carbon atoms, halogens, cyano groups, nitro groups, amino groups, substituted alkyl groups, substituted alkoxy groups, and substituted amino groups; The alkyl group in the substituted alkyl group is an alkyl group with 1 to 3 carbon atoms, and the substituent group is a halogen. The alkoxy group in the substituted alkoxy group is an alkoxy group with 1 to 3 carbon atoms, and the substituent group is a halogen. The substituent group in the substituted amino group is an alkyl group with 1 to 3 carbon atoms or an acyl group with 2 to 4 carbon atoms; X1 and X2 are N, O, or S.

[0008] The heteroalkyl group described in this invention refers to an alkyl group containing at least one heteroatom.

[0009] In a second aspect, the present invention provides a pharmaceutical composition comprising an effective dose of the 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative of the first aspect or a pharmaceutically acceptable salt, solvate, racemate, or optical isomer thereof.

[0010] Thirdly, the present invention provides a pharmaceutical formulation comprising the above-mentioned 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative or pharmaceutical composition, and at least one pharmaceutically acceptable carrier or excipient.

[0011] Fourthly, the present invention provides the use of the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative, pharmaceutical composition or pharmaceutical preparation in the preparation of bacterial quorum sensing inhibitors or antibacterial sensitizers.

[0012] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows: (1) The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative of the present invention has no effect on the growth of a variety of sensitive and drug-resistant bacteria and is not easily induced to produce drug resistance.

[0013] (2) The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative of the present invention against Pseudomonas aeruginosa pqs The system has a significant interfering effect, and this effect increases with increasing concentration.

[0014] (3) The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative of the present invention has a good biofilm formation inhibition effect.

[0015] (4) The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative of the present invention has good antibacterial synergistic effect in in vitro experiments. Attached Figure Description

[0016] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0017] Figure 1 The figure shows the results of the investigation of the inhibitory activity of compounds B1~B36 on biofilm formation of Pseudomonas aeruginosa PAO1 in the embodiments of the present invention. A represents compounds B1~B8, B represents compounds B9~B20, C represents compounds B21~B26, and D represents compounds B27~B36. Figure 2This diagram illustrates the synergistic antibacterial effects of compounds B25 and B32 with the antibacterial agents tobramycin (TOB), clarithromycin (CLA), or ciprofloxacin (CIP) in embodiments of the present invention. A represents compound B25 with TOB, B represents compound B32 with TOB, C represents compound B25 with CLA, D represents compound B32 with CLA, E represents compound B25 with CIP, and F represents compound B32 with CIP. Figure 3 Compound B32 in the embodiments of the present invention is used to treat PAO1. -gfp (A) PAO1- lasB-gfp (B) PAO1- rhlA- gfp (C) and PAO1- pqsA-gfp (D) Graph showing the results of the investigation of inhibitory activity. Detailed Implementation

[0018] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0019] To address the crisis exacerbated by antibiotic overuse as mentioned in the background section, particularly by Pseudomonas aeruginosa (… Pseudomonas aeruginosa Nosocomial infections caused by Gram-negative bacteria, such as α, are particularly challenging, and their multidrug resistance characteristics pose a serious challenge to clinical treatment. The first aspect of this invention provides a 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative having the chemical structure shown in general formula A. ; Among them, R 1 Selected from alkyl groups having 1 to 10 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, substituted or unsubstituted aryl groups containing 5 to 10 main chain atoms, or aromatic heteroyl groups. ; In this context, n is 0 to 4, and Z is selected from three to eight-membered cycloalkyl, three to eight-membered cyclohexaalkyl, or substituted or unsubstituted aryl and aromatic heteroalkyl containing 5 to 10 main chain atoms; R 1 The substituted aryl or substituted aromatic heterol groups in Z are monosubstituted or polysubstituted by any of the following substituents: alkyl with 1-9 carbon atoms, heteroalkyl with 1-9 carbon atoms, halogen, cyano, nitro, amino, substituted alkyl, substituted alkoxy and substituted amino; Y1, Y2, Y3, Y4, and Y5 are independently selected from N, CH, and C(R), respectively. 2 ), R 2Selected from alkyl groups having 1 to 3 carbon atoms, heteroalkyl groups having 1 to 3 carbon atoms, halogens, cyano groups, nitro groups, amino groups, substituted alkyl groups, substituted alkoxy groups, and substituted amino groups; The alkyl group in the substituted alkyl group is an alkyl group with 1 to 3 carbon atoms, and the substituent group is a halogen. The alkoxy group in the substituted alkoxy group is an alkoxy group with 1 to 3 carbon atoms, and the substituent group is a halogen. The substituent group in the substituted amino group is an alkyl group with 1 to 3 carbon atoms or an acyl group with 2 to 4 carbon atoms; X1 and X2 are N, O, or S.

[0020] The heteroalkyl group described in this invention refers to an alkyl group containing at least one heteroatom.

[0021] In some embodiments, the aromatic heterol group is selected from furanyl, pyrroleyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl, pyrazolyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, carbazoleyl, purinyl, phenothiazinyl, or phenothiazinyl.

[0022] In some embodiments, the aryl group is phenyl.

[0023] In some embodiments, the substituents for substituted aryl or substituted aromatic heteroyl groups are straight-chain alkyl groups with 1 to 9 carbon atoms, branched alkyl groups with 1 to 9 carbon atoms, heteroalkyl groups with 1 to 9 carbon atoms, or cycloalkyl groups with 3 to 8 carbon atoms.

[0024] In some embodiments, in the substituents of the aryl or aryl heterol groups, the substituted alkyl group is in which one or more hydrogen atoms in the alkyl group are replaced by a halogen, such as fluoromethyl, fluoroethyl, difluoromethyl, and trifluoromethyl. The substituted alkoxy group is an alkoxy group in which one or more hydrogen atoms are replaced by halogens, such as monofluoromethoxy, monofluoroethoxy, difluoromethoxy, and trifluoromethoxy. The substituted amino group is a primary amino group in which one or both hydrogen atoms are replaced by an alkyl or acyl group. Examples include methylamino, dimethylamino, and acetamino.

[0025] In some implementations, Y1, Y2, Y3, and Y4 contain at most three N atoms. The groups in general formula A... Selected from the following structure: , , , , , , , , , , , , , , , , .

[0026] In some implementations, the group in general formula A for or .

[0027] In some embodiments, the structure of the 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative is shown in general formula B: ; Among them, R 1 Y5 and X1 are as described above. This invention verifies, through general formula B, that the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative has good efficacy.

[0028] Preferably, in compound B, X1 is O or S, and R... 1 It is an alkyl group having 4 to 10 carbon atoms, or a substituted or unsubstituted aryl or aromatic heterol group containing 5 to 10 main chain atoms. .

[0029] In some embodiments, the 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative is selected from compounds with the following structures: .

[0030] Thirdly, a pharmaceutical composition is provided, comprising an effective dose of the 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative of the first aspect or a pharmaceutically acceptable salt, solvate, racemate, or optical isomer thereof.

[0031] In the present invention, the pharmaceutical composition is used to prepare an antibacterial agent, and the effective dose is the drug dose required to achieve antibacterial activity, which can be determined by conventional methods in the art.

[0032] In some embodiments, the pharmaceutical composition further includes other antibacterial active ingredients, which may be antibiotics such as ciprofloxacin, polymyxin, clarithromycin, tobramycin, etc.

[0033] The pharmaceutically acceptable salts described in this invention can be salts formed with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, or hydrobromic acid); or salts formed with organic acids (such as methanesulfonic acid, toluenesulfonic acid, or trifluoroacetic acid).

[0034] The solvate of the present invention can be an organic solvate of a 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative, or a hydrate of a 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative.

[0035] Fourthly, a pharmaceutical formulation comprising the above-described 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative or pharmaceutical composition, with at least one pharmaceutically acceptable carrier or excipient.

[0036] The pharmaceutically acceptable carriers or excipients described in this invention are non-toxic and safe, and their combination with the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivatives described in this invention is also non-toxic and safe. The pharmaceutically acceptable carriers and excipients described in this invention are generally well known to those skilled in the art, or can be determined by those skilled in the art based on the specific circumstances. Examples of suitable carriers and excipients include glucose, water, lactose, sucrose, glycerol, ethanol, propylene glycol, mannitol, corn starch, gelatin, alginate, microcrystalline cellulose, kaolin, dicalcium phosphate, sodium chloride, croscarmellose sodium, and sodium starch glycolate, etc.; hydrophilic carriers, hydrophobic carriers, or combinations thereof, etc. Hydrophobic carriers include, for example, fat emulsions, lipids, polyethylene glycol-modified phospholipids, biocompatible polymers, lipospheres, liposomes, microvesicles, polymer matrices, and particles, etc. Furthermore, those skilled in the art will understand that diluents are included within the scope of the terms carriers and excipients. For convenience, local anesthetics, preservatives, buffers, etc., can be directly dissolved in the carrier.

[0037] The pharmaceutical compositions and formulations of the present invention can be administered in unit doses, and the dosage forms include injections, tablets, pills, capsules, suspensions, emulsions, aerosols, powders, lyophilized powder injections, inclusion complexes, implants, patches, and liniments. These dosage forms can be prepared by adding suitable excipients or formulations according to conventional methods in the art.

[0038] Fifthly, the use of the above-mentioned 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative, pharmaceutical composition or pharmaceutical preparation in the preparation of bacterial quorum sensing inhibitors.

[0039] When 3-(2-thiazol-5-ylmethyl)benzoxazolone derivatives are used as bacterial quorum sensing inhibitors, they can inhibit the QS system of Gram-negative bacteria, thereby inhibiting bacterial biofilm formation and reducing the expression of bacterial virulence factors. Therefore, the bacterial quorum sensing inhibitors described in this invention can be used not only as bacteriostatic agents, bacteriostatic drugs, or antibacterial drugs for therapeutic purposes, but also as chemical agents for scientific research on the inhibition of bacterial biofilms.

[0040] In some embodiments, the bacteria are Gram-negative bacteria, including but not limited to *Pseudomonas aeruginosa*, *Acinetobacter* spp., *Escherichia coli*, *Klebsiella pneumoniae*, *Vibrio cholerae*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, *Legionella pneumophila*, *Bordetella pertussis*, *Proteus*, *Shigella*, *Brucella*, *Moraxella catarrhalis*, *Yersinia* spp., *Bordetella parapertussis*, *Shigella* spp., *Pasteurella* spp., and *Bacillus parahaemolyticus*. Bacterial biofilm formation inhibition experiments showed that the above-mentioned 3-(2-thiazol-5-ylmethyl)benzoxazolone derivatives had a strong inhibitory effect on *Pseudomonas aeruginosa* PAO1 biofilms. Combined use with antibacterial drugs significantly improved the sensitivity of drug-resistant bacteria to the antibiotics ciprofloxacin, clarithromycin, and tobramycin, enhancing drug efficacy. QS fluorescent reporter strain experiments showed that the compound could inhibit [the growth of bacteria] in a concentration-dependent manner. pqsA The fluorescence expression indicates that the compound may directly act on... pqs Quorum sensing system. Therefore, the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative of the present invention can effectively reduce the toxicity and drug resistance of the above-mentioned Gram-negative bacteria, and thus be used for the treatment of diseases caused by Gram-negative bacteria, or for the preparation of drugs for treating diseases caused by Gram-negative bacteria.

[0041] Furthermore, the diseases mentioned include, but are not limited to, pneumonia, cystic fibrosis, endocarditis, peritonitis, empyema, sepsis, cholecystitis, cystitis, diarrhea, gastroenteritis, etc.

[0042] Sixthly, a method for treating, alleviating, or preventing diseases such as pneumonia, cystic fibrosis, endocarditis, peritonitis, empyema, sepsis, cholecystitis, cystitis, diarrhea, and gastroenteritis caused by Gram-negative bacteria, said method comprising administering a therapeutically effective amount of the above-mentioned 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivative or pharmaceutical composition or pharmaceutical preparation.

[0043] Seventhly, the application of the above-mentioned 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative in the preparation of antibacterial sensitizers.

[0044] The structure of 3-(2-thiazolyl-5-ylmethyl)benzoxazolone derivatives is shown in general formula B: ; When X1 is 0 or S, R 1 for Where n is 0-4, and Z contains 5 to 10 substituted or unsubstituted aryl and aromatic heteroyl groups of the main chain, the preparation route is shown below: .

[0045] The preparation method includes the following steps: (1) Using acyl chloride and ammonia as raw materials, the mixture was dissolved in water and subjected to an amide condensation reaction at 0 °C. After stirring for 8 h, compound 2 was obtained by silica gel column chromatography.

[0046] (2) Compound 2 was dissolved in redistilled tetrahydrofuran, Lawson's reagent was added, and the mixture was stirred at room temperature for 18 h under nitrogen protection. After the reaction was complete, the solvent was evaporated to dryness. The solution was dissolved in dichloromethane, transferred to -2 °C, and then slowly quenched with water and extracted. The solution was evaporated to dryness under reduced pressure. Compound 3 was obtained by silica gel column chromatography.

[0047] (3) Compound 3 reacted with 1,3-dichloroacetone in an ethanol solution to undergo a cyclization reaction. The mixture was stirred at 50 °C for 18 h. The solution was evaporated to dryness under reduced pressure and purified by silica gel column chromatography to obtain compound 4.

[0048] (4) Add compound 5 to a 250 mL round-bottom flask, dissolve it in acetonitrile, and then slowly add N,N' -Dicarbonylimidazolium, under nitrogen protection, heated to 70 °C and stirred for 18 h. The mixture was evaporated to dryness under reduced pressure and purified by silica gel column chromatography to obtain compound 6.

[0049] (5) Compound 6 and compound 4 were subjected to a nucleophilic substitution reaction, with cesium carbonate as an acid-binding agent, and purified by column chromatography to obtain the corresponding compound 7 of type B.

[0050] Compound B, when the R 2 For H and Cl, the R 1 The preparation routes for alkyl groups with 4 to 10 atoms, substituted or unsubstituted aryl or aromatic heteroyl groups containing 5 to 10 main chain atoms are shown below: .

[0051] The preparation method includes the following steps: (1) Using benzimidazolone 8 with different substitutions as raw material, it is dissolved in tetrahydrofuran. Sodium hydrogen and diethyl pyrocarbonate are slowly added at 0°C to carry out N-ethoxycarbonylation reaction. The mixture is stirred at 25°C for 18 h and purified by silica gel column chromatography to obtain brown solid 9. Preferably, in step a, the carbonylation reagent is diethyl pyrocarbonate (1 equivalent).

[0052] (2) Compound 9 was dissolved in acetonitrile solution, and potassium carbonate and chloroacetone were added sequentially. Under nitrogen protection, the mixture was stirred at 80 °C for 18 h. After the reaction was complete, the solvent was evaporated. The mixture was dissolved and extracted with dichloromethane, and purified by silica gel column chromatography to obtain compound 10. Preferably, in step b, the base is potassium carbonate (1-1.5 equivalents), the reaction temperature is 80 °C, and the reaction time is 18 h.

[0053] (3) Compound 10 was dissolved in acetonitrile solution, and azobisisobutyronitrile, N-bromosuccinimide, and hydrobromic acid aqueous solution were added sequentially. The mixture was stirred at 50 °C for 18 h. After the reaction was complete, intermediate 11 was directly evaporated to dryness and added to the next step without purification. Preferably, in step c, the brominating reagents were azobisisobutyronitrile (0.1 equivalent), N-bromosuccinimide (1.1 equivalent), and hydrobromic acid aqueous solution (10 volumes), the reaction temperature was 50 °C, and the reaction time was 18 h.

[0054] (4) Compound 11 was dissolved in anhydrous ethanol, and different substituted thioamides were added. Under nitrogen protection, the mixture was stirred at 50 °C for 18 h. After the reaction was complete as detected by TLC, compound 12 was obtained by extraction, washing and drying, and silica gel column purification.

[0055] (5) Compound 12 underwent a β-elimination reaction in the presence of sodium ethoxide, removing the ethoxycarbonyl group, and was purified by column chromatography to obtain the corresponding compound 13 of type B.

[0056] Preferably, the compound shown in formula B is X1 is N, O, or S, R 2 The preparation routes for H, CH3, NO2, F, CN, CF3, Cl, and Br are shown below: .

[0057] The preparation method includes the following steps: (1) Using ethyl 2-bromothiazol-5-carboxylate 14 as a raw material, it is dissolved in ethanol, and sodium borohydride is added at 0 °C to carry out a reduction reaction. After stirring for 2 h, the product is purified by silica gel column chromatography to obtain a yellow oily substance 15. Preferably, in step a, the reducing agent is sodium borohydride (2-3.4 equivalents).

[0058] (2) Compound 15 was dissolved in a solution of dioxane and water (10:1), and potassium carbonate, boric acid, and tetratetraphenylphosphine palladium were added sequentially. Under nitrogen protection, the mixture was stirred at 80 °C for 36 h. After the reaction was complete, the solvent was evaporated. The mixture was dissolved and extracted with dichloromethane, and purified by silica gel column chromatography to obtain compound 16. Preferably, in step b, the base is potassium carbonate (10 equivalents), the catalyst is tetratetraphenylphosphine palladium (0.06 equivalents), the reaction temperature is 80 °C, and the reaction time is 36 h.

[0059] (3) Compound 16 was dissolved in dichloromethane solution, and phosphorus tribromide was slowly added dropwise at 0-25 °C with stirring for 2 h. After the reaction was completed, water was slowly added dropwise at 0 °C to quench the reaction, followed by extraction and purification to obtain compound 17.

[0060] (4) Compounds 6 and 17 underwent a nucleophilic substitution reaction, with cesium carbonate acting as an acid-binding agent. After the reaction was complete, water was added to quench the reaction, followed by extraction and evaporation under reduced pressure. The resulting compound was purified by column chromatography to obtain the corresponding compound B, 18.

[0061] To enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0062] Unless otherwise specified, the raw materials and reagents used in this invention can be purchased through conventional channels or prepared according to methods known in the art, or prepared by those skilled in the art through conventional experiments. Furthermore, any methods and materials similar to or equivalent to those described herein can be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0063] Example 1 Synthesis of phenylpropionamide intermediate 2 ; Weigh out 50 mL of ammonia solution (25%) and dissolve it in 50 mL of water. Add 10 g (59.30 mmol) of phenylpropionyl chloride 1 dropwise at 0 °C, then transfer to room temperature and stir for 2 h. After the reaction is complete as monitored by TLC, extract repeatedly with an appropriate amount of ethyl acetate, combine the organic phases, and concentrate under reduced pressure. Wash three times with saturated brine, dry to anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain the crude product. Purify by silica gel column chromatography (eluent: petroleum ether-ethyl acetate, 5:1-2:1) to obtain compound 2, 6.46 g of white solid (yield 73%).

[0064] Example 2 Synthesis of thiophenylpropionamide intermediate 3 ; The product obtained in Example 1 (6.46 g, 43.30 mmol) and Lawson's reagent (17.51 ​​g, 43.30 mmol) were dissolved in redistilled tetrahydrofuran (120 mL) under nitrogen protection and stirred at room temperature for 18 h. After the reaction was complete as detected by TLC, the solvent was evaporated to dryness. The solution was dissolved in dichloromethane, quenched with water, and then extracted with dichloromethane. The organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate, 3:1) to give compound 3, a pale yellow solid, in 7.08 g, with a yield of 99%.

[0065] Example 3 Synthesis of 4-(chloromethyl)-2-phenylethylthiazole intermediate 4 ; The product obtained in Example 2 (4.00 g, 24.21 mmol) was dissolved in anhydrous ethanol, and 1,3-dichloropropanone (3.07 g, 24.21 mmol) was added. The mixture was heated to 50 °C and stirred for 18 h. After the reaction was completed as detected by TLC, the reaction was stopped, the solution was evaporated to dryness, and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 40:1) to give compound 4, 2.59 g of a colorless oil, with a yield of 45%.

[0066] Example 4 6-Methylbenzo[a] [d] Oxazole-2(3) H Synthesis of 6-keto intermediate ; Add 6-aminom-cresol (4 g, 32.48 mmol) to a 100 mL round-bottom flask, dissolve in 40 mL acetonitrile, and then add... N,N' -Carbonyldiimidazole (7.88 g, 48.72 mmol). The reaction system was heated to 70 °C and stirred for 18 h. After the reaction was completed by TLC monitoring, the mixture was evaporated to dryness. The residue was diluted with water and then extracted with ethyl acetate. The organic layers were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure and purified by pulping (using 40 v / v of water) to give compound 6, a light brown solid of 5.16 g, in 85% yield.

[0067] Example 5 Synthesis of compound (B25) shown in Formula B ; Product 6 (200 mg, 1.34 mmol) obtained in Example 4 was dissolved in 5 mL of redistilled tetrahydrofuran, and cesium carbonate (873.8 mg, 2.68 mmol) was added, followed by compound 4 (318.8 mg, 1.34 mmol). The mixture was heated to 50 °C and stirred for 18 h. After the reaction was completed as detected by TLC, the reaction was stopped, the solution was evaporated to dryness, and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 10:1-8:1-5:1) to obtain compound B25, a yellow solid of 176 mg, with a yield of 37%. The structural confirmation information of the compounds is shown in Table 1.

[0068] The preparation process of compounds B1~B8 and B21~B26 is the same as that for preparing B25, only requiring the corresponding replacement of the raw materials.

[0069] Example 6 2-Oxo-2,3-Dihydro-1 H -Benzo [d] Synthesis of intermediate 9 of imidazole-1-carboxylic acid ethyl ester ; Take 1,3-dihydro-2 H -Benzo [d] Imidazol-2-one 8 (3 g, 22.36 mmol) dissolved in 60 mL N,N' In dimethylformamide, 60% sodium hydride (1.79 g, 44.73 mmol) was added at 0 °C, followed by diethyl pyrocarbonate (3.63 g, 22.36 mmol) under nitrogen protection. The mixture was then transferred to room temperature and stirred for 18 h. After the reaction was complete as determined by TLC, the reaction was stopped, and the mixture was washed with water, extracted with ethyl acetate, and evaporated to dryness to obtain the crude product. Purification by silica gel column chromatography (petroleum ether-ethyl acetate, 5:1–3:1) yielded compound 9, a white solid, 3.84 g, in 78% yield.

[0070] Example 7 2-Oxo-3-(2-Oxopropyl)-2,3-Dihydro-1 H -Benzo [d] Synthesis of intermediate 10 of imidazole-1-carboxylic acid ethyl ester

[0071] Product 9 (3.84 g, 18.62 mmol) obtained in Example 6 was dissolved in acetonitrile (80 mL), followed by the addition of potassium carbonate (3.09 g, 22.35 mmol) and chloroacetone (2.58 g, 27.93 mmol). The mixture was heated to 80 °C and stirred for 18 h under nitrogen protection. After the reaction was complete as detected by TLC, the solvent was evaporated to dryness. The product was dissolved in dichloromethane, quenched with water, and then extracted with dichloromethane. The organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate, 3:1) to give compound 10, a brown solid (3.08 g), in 63% yield.

[0072] Example 8 2-Oxo-3-((2-phenylethylthiazo-4-yl)methyl)-2,3-dihydro-1 H -Benzo [d] Synthesis of intermediate 12 of imidazole-1-carboxylic acid ester ; Product 10 (200 mg, 0.76 mmol) obtained in Example 7 was dissolved in 5 mL of acetonitrile, and azobisisobutyronitrile (12.5 mg, 0.08 mmol) was added sequentially. N- Succinimide bromide (149.3 mg, 0.84 mmol) and 48% hydrobromic acid aqueous solution (2 mL), under nitrogen protection, were heated to 50 °C and stirred for 18 h. After the reaction was complete, the mixture was directly evaporated to dryness to obtain intermediate 11. Compound 11 was dissolved in anhydrous ethanol, and phenylpropylthioamide 3 was added. Under nitrogen protection, the mixture was heated to 50 °C and stirred for 18 h. After the reaction was confirmed to be complete by TLC, the mixture was extracted, washed, and dried, and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 2:1-1:1) to obtain compound 12, a white solid of 170.2 mg, in a yield of 55%.

[0073] Example 9 Synthesis of compound (B20) shown in Formula B ; Product 12 (100 mg, 0.25 mmol) obtained in Example 8 was dissolved in 5 mL of ethanol, and sodium ethoxide (16.7 mg, 0.25 mmol) was added. The mixture was stirred at 25 °C for 18 h. After the reaction was completed as detected by TLC, the reaction was stopped, the solution was evaporated to dryness, and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 2:1-1:1) to obtain compound B20, a white solid of 65.4 mg, with a yield of 78%. The relevant structural confirmation information of the compound is shown in Table 1.

[0074] The preparation process of compounds B9 to B19 is the same as that for preparing B20, only requiring the corresponding replacement of the raw materials.

[0075] Example 10 Synthesis of 2-bromothiazole-5-methanol intermediate 15 ; Ethyl 2-bromothiazol-5-carboxylate (25 g, 105.90 mmol) was dissolved in anhydrous ethanol. Sodium borohydride (8.01 g, 211.79 mmol) was slowly added at -10 °C under nitrogen protection. The temperature and balloon volume were monitored after addition, and gas was released promptly. The reaction was then stirred at this temperature for 2 h. After the reaction was confirmed by TLC, it was stopped, and then quenched by slow dropwise addition of 200 mL of 2M sodium hydroxide solution at -10 °C. The mixture was then extracted multiple times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. Purification by silica gel column chromatography (petroleum ether-ethyl acetate, 3:1) yielded compound 16, a yellow oil of 16.46 g, in 80% yield.

[0076] Example 11 Synthesis of intermediate 16 of (2-(3-chloro-4-isopropoxyphenyl)thiazolyl-5-yl)methanol ; 2-Bromothiazol-5-methanol 15 (2 g, 10.31 mmol) was dissolved in dioxane-water solution (10:1). Potassium carbonate (7.12 g, 51.53 mmol), 3-chloro-4-isopropoxyphenylboronic acid (2.21 g, 10.31 mmol), and tetraphenylphosphine (714.6 mg, 0.62 mmol) were added sequentially at 80 °C under nitrogen protection. The reaction was then stirred for 36 h at this temperature. After the reaction was complete as detected by TLC, the reaction was stopped, and the organic phase was evaporated to dryness. The mixture was then extracted several times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. Purification by silica gel column chromatography (petroleum ether-ethyl acetate, 3:1-2:1-1:1) yielded compound 16, 1.61 g of purple solid, in a yield of 55%.

[0077] Example 12 Synthesis of 5-(bromomethyl)-2-(3-chloro-4-isopropoxyphenyl)thiazole intermediate 17 ; Dissolve 1.4 g (4.93 mmol) of (2-(3-chloro-4-isopropoxyphenyl)thiazol-5-yl)methanol in dichloromethane under nitrogen protection. Add 6.68 g (24.67 mmol) of phosphorus tribromide dropwise at 0 °C. Then, stir the reaction mixture at 25 °C for 2 h. Stop the reaction after TLC detection of completion. Quench the reaction by slow dropwise addition of saturated sodium bicarbonate solution at 0 °C, followed by multiple extractions with dichloromethane. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Extract with ethyl acetate multiple times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness to obtain 2.41 g of crude product. Dissolve in ultra-dry tetrahydrofuran; no purification is required, and proceed directly to the next step.

[0078] Example 13 Synthesis of compound (B32) shown in Formula B ; Product 5 (100 mg, 0.56 mmol) obtained in Example 5 was dissolved in 5 mL of redistilled tetrahydrofuran, and cesium carbonate (361.8 mg, 1.11 mmol) was added, followed by compound 17 (192.5 mg, 0.56 mmol). The mixture was heated to 50 °C and stirred for 18 h. After the reaction was completed as detected by TLC, the reaction was stopped, the solution was evaporated to dryness, and purified by silica gel column chromatography (petroleum ether-ethyl acetate, 10:1-8:1) to obtain compound 13, a yellow solid of 47.4 mg, with a yield of 19%. The structural confirmation information of the compounds is shown in Table 1.

[0079] The preparation process of compounds B27 to B36 is the same as that of B32, only requiring the corresponding replacement of the raw materials.

[0080] Table 1. Structural confirmation information for compounds B1-B36

[0081] Example 13 Effects of derivatives B1-B36 on biofilm formation of Pseudomonas aeruginosa PAO1 This embodiment measures the effect of target compounds (B1~B36) on Pseudomonas aeruginosa (…). P. aeruginosa The effect of PAO1 on biofilm formation was used to characterize the QS inhibition intensity of the compounds of this invention. The bacterial strains used were obtained from the China General Microbiological Culture Collection Center (CGMCC).

[0082] Experimental methods: Pseudomonas aeruginosa PAO1 was revived, passaged into LB broth, and incubated at 37 ℃ for 20 h in a constant temperature biochemical incubator. The passaged PAO1 was diluted to OD using ABTGC medium. 620 = 0.05. Add an appropriate amount of the above bacterial culture and the stock solution of the test compound to the 96-well plate, dilute twice to 32 μg / mL, so that each well contains 100 μL. Perform three replicates for each sample, and set up a negative control and a blank control group. Seal the experimental wells with 200 μL of broth to prevent edge effects. Incubate in a 37℃ biochemical incubator for 24 h. Afterward, discard the liquid in the wells, trying not to touch the sides and bottom to avoid damaging the biofilm and affecting the experimental results. Wash twice with 150 μL of PBS buffer, then add 100 μL of anhydrous methanol and retain for 30 min to fix the biofilm. Then discard the methanol and dry in a 30℃ oven. Add 100 μL of 0.1% crystal violet solution and retain for 15 min to stain the biofilm. Discard the stain and wash the 96-well plate repeatedly with PBS until the washing water is colorless. Then dry the 96-well plate. Finally, add 100 μL of 33% glacial acetic acid solution to the 96-well plate, shake for 5-10 min, and after the biofilm is completely dissolved, measure the OD. 570 The biofilm formation inhibition rate was 1-(Abs) sample -Abs blank ) / (Abs negative -Abs blank ) × 100%.

[0083] Depend on Figure 1 As shown in A, among compounds B1-B8, compound B3 exhibits the best activity, with a biofilm residue level only 41.71 ± 6.84% of the negative control. Figure 1 As shown in B, among compounds B9-B20, compound B20 exhibits the best inhibitory effect on biofilm formation. After treatment with compound B20, the residual biofilm content of bacteria was 34.42 ± 2.38%, with an inhibition rate greater than 65%. Figure 1 As shown in C, among compounds B20-B26, most exhibited strong inhibitory effects on biofilm formation, with compound B22 showing the best activity, exhibiting a biofilm residue of only 26.17 ± 0.60% of the negative control. Figure 1 According to D, among compounds B27 to B36, compound B32 has the best activity, with a biofilm residue of 12.59 ± 2.15% of the negative control, which is superior to the positive control azithromycin AZM.

[0084] Example 14 Synergistic antibacterial effect of derivatives B25 and B32 with antibacterial agents Experimental Methods: Resuscitate Pseudomonas aeruginosa PAO1 and streak it onto solid culture medium. Incubate the medium at 37℃ for 20 h. Add 6-8 mL of physiological saline to a turbidity tube. Use an inoculation loop to transfer well-preserved subculture colonies into the turbidity tube and mix to a final volume of 1.5 × 10⁻⁶. 8 CFU / mL. Take 2 mL of bacterial suspension and add 18 mL of physiological saline to obtain bacterial solution. Take a sterile 96-well plate and add 187.5 µL of liquid culture medium to column 2, and 95 µL of liquid culture medium to columns 3-6. Add 10 µL of antibiotic stock solution to column 2, and 5 µL of antibiotic stock solution to columns 3-6. Add 2.5 µL of the test compound to column 2 until the compound concentration reaches 32 μg / mL. Mix the culture medium and compound in column 2, and add 100 µL to the next column, mixing well. Repeat this mixing process until column 5, discarding any excess 100 µL. At this point, each column has a volume of 100 µL. The drug concentration decreases by a factor of 2 from 32-4 μg / mL from columns 2-5. The antibiotics used are tobramycin, clarithromycin, and ciprofloxacin (final concentrations of 1 / 4 MIC, 1 / 8 MIC, 1 / 16 MIC, 1 / 32 MIC, and 1 / 64 MIC). Add 5 µL of bacterial suspension to columns 2-6. Set up a negative control (culture medium + DMSO + bacterial suspension) for each group, and surround it with 200 µL of liquid culture medium. LB medium was used for edge sealing to prevent edge effects and serve as a blank control. Three parallel experiments were conducted for each sample. The 96-well plates were incubated at 37 °C for 20 h. After incubation, the plates were shaken for 30 s in a microplate reader, and the optical density (OD) was read. 600). Calculate bacterial mortality rate: 1 - (Abs) sample -Abs blank ) / (Abs negative -Abs blank )× 100%.

[0085] Depend on Figure 2 It was found that different concentrations of compounds B25 and B32, when used in combination with sub-inhibitory concentrations of tobramycin, clarithromycin, and ciprofloxacin, were more effective in inhibiting bacterial activity than the same concentrations of antibiotics used alone. Among these, the combination of B32 with tobramycin, clarithromycin, and ciprofloxacin showed better sensitization effects against Pseudomonas aeruginosa PAO1, with inhibition rates of 79.83%, 83.42%, and 94.08%, respectively.

[0086] Example 15: Derivative B32 on GFP reporter strain PAO1- lasB-gfp , PAO1- rhlA-gfp , PAO1- pqsA-gfp and PAO1- gfp Inhibitory activity This embodiment measures the effect of target compound B32 on the GFP reporter strain PAO1- lasB-gfp , PAO1- rhlA- gfp , PAO1- pqsA-gfp and PAO1- gfp Inhibition activity characterizes the targeting of the compounds of this invention to quorum sensing systems.

[0087] Experimental Methods: The test compound B32 was diluted to concentrations of 32, 16, 8, and 4 μg / mL in 96-well plates using the two-fold dilution method. 75 μL of liquid culture medium containing different concentrations of the compound and 75 μL of overnight incubation solution were added to each well of the 96-well plate and then diluted to OD. 600 The bacterial culture concentration was 0.05. The 96-well plate was placed in a multi-mode microplate detection system, with the temperature set at 37 ℃, excitation wavelength at 485 nm, and emission wavelength at 528 nm. Fluorescence intensity and OD were measured every 15 min. 600 The effects of the compound on the three QS pathways were determined by continuously measuring for 4 hours and calculating the ratio of fluorescence intensity to absorbance.

[0088] Depend on Figure 3 It can be seen that compound B32 can inhibit PAO1- in a concentration-dependent manner. lasB-gfp and PAO1- pqsA- gfp Fluorescent expression, but does not affect PAO1- rhlA-gfp and PAO1- gfp The fluorescence indicates that the compound can target quorum sensing. las and pqs Instead of acting directly on green fluorescent protein, this experimental result more directly demonstrates the targeting ability of our newly synthesized compound for quorum sensing systems, indicating that our newly synthesized compound can be effectively used as a QSI for the treatment of bacterial infections.

[0089] The above results indicate that the target compound can be effectively used as a quorum sensing inhibitor for the treatment of bacterial infections.

[0090] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative, characterized in that: which has a chemical structure shown in general formula A; ； wherein R 1 selected from an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aryl group, heteroaryl group, or heteroaromatic group containing 5 to 10 main chain atoms, and ; wherein n is 0-4 and Z is selected from a three- to eight-membered cycloalkyl, a three- to eight-membered cycloheteroalkyl, or a substituted or unsubstituted aryl and arhetero group containing 5 to 10 main chain atoms; R 1 and the substituted aryl group or substituted arahetero group in Z is mono- or poly-substituted with any of a C1-9alkyl group, a C1-9heteroalkyl group, a halogen, a cyano group, a nitro group, an amino group, a substituted alkyl group, a substituted alkoxy group, and a substituted amino group; Y1, Y2, Y3, Y4and Y5are each independently selected from N, CH and C(R 2 ), R 2 selected from an alkyl group having 1 to 3 carbon atoms, a heteroalkyl group having 1 to 3 carbon atoms, a halogen, a cyano group, a nitro group, an amino group, a substituted alkyl group, a substituted alkoxy group, a substituted amino group; the alkyl in the substituted alkyl is alkyl with 1-3 carbon atoms, and the substituent is halogen; the alkoxy in the substituted alkoxy is alkoxy with 1-3 carbon atoms, and the substituent is halogen; the substituent in the substituted amino is alkyl with 1-3 carbon atoms or acyl with 2-4 carbon atoms; X1, X2 are N or O or S.

2. The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative according to claim 1, characterized by: the aromatic hetero group is selected from furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, morpholinyl, pyrazolyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, carbazolyl, purinyl, phenothiazinyl or phenoxazinyl; or, the aryl group is phenyl.

3. The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative according to claim 1, characterized by: the substituent of the substituted aryl or substituted aromatic hetero group is linear alkyl with 1-9 carbon atoms, branched alkyl with 1-9 carbon atoms, heteroalkyl with 1-9 carbon atoms, or cycloalkyl with 3-8 carbon atoms; or, the substituent of the substituted aryl or substituted aromatic hetero group, the substituted alkyl is alkyl in which one or more hydrogens are substituted by halogen; the substituted alkoxy is alkoxy in which one or more hydrogens are substituted by halogen; the substituted amino is primary amino in which one or both hydrogens are substituted by alkyl or acyl; or, at most three of Y1, Y2, Y3and Y4contain N, wherein the group is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； or the group in general formula A is , or .

4. The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative according to claim 1, characterized by: the structure of the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative is shown in general formula B: ； wherein R 1 , Y5and X1are as recited in claim 1.

5. The 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative according to claim 4, characterized by: In the compound of formula B, X1is O or S, R 1 is an alkyl group having 4 to 10 carbon atoms, a substituted or unsubstituted aryl group, aryl hetero group or ; preferably, the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative is selected from the following compounds: 。 6. A pharmaceutical composition, characterized by: a pharmaceutical composition comprising an effective amount of the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative or a pharmaceutically acceptable salt, solvate, racemate or optical isomer thereof according to any one of claims 1-5.

7. The pharmaceutical composition of claim 6, wherein: the pharmaceutical composition further comprises other components with antibacterial activity.

8. A pharmaceutical preparation, characterized by: a pharmaceutical composition comprising the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative or a pharmaceutically acceptable salt, solvate, racemate or optical isomer thereof according to any one of claims 1-5, and at least one pharmaceutically acceptable carrier or excipient.

9. Use of the 3-(2-thiazol-5-ylmethyl)benzoxazolone derivative according to any one of claims 1-5, the pharmaceutical composition according to claim 6 or 7, or the pharmaceutical preparation according to claim 7 in the preparation of a bacterial quorum sensing inhibitor or an antibacterial sensitizer.

10. Use according to claim 9, characterized in that: the bacteria are gram-negative bacteria including but not limited to Pseudomonas aeruginosa, Acinetobacter, Escherichia coli, Klebsiella pneumoniae, Vibrio cholerae, Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Bordetella pertussis, Proteus, Shigella, Pasteurella, Yersinia, Bordetella parapertussis, Shigella, Pasteurella or Parahemolyticus.

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