4-(4-fluorophenyl)-1, 5-dihydroxy-5-methyl pyrrolidone derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a 4-(4-fluorophenyl)-1, 5-dihydroxy-5-methyl pyrrolidone derivative as well as a preparation method and application thereof. The compound is shown in a formula I; r1 is selected from alkyl, heteroalkyl, cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; n is an integer of 0-6, Y is methylene, O or S, and Z is selected from cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; a represents a methylene group, a sulfuryl group, or a carbonyl group. As a novel pseudomonas aeruginosa quorum sensing inhibitor, the derivative provided by the invention not only can interfere iron uptake of bacteria, but also has antibacterial and sensitizing effects.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Pathogens' inherent defense mechanisms, combined with the widespread use and misuse of antibiotics, have made even common infections difficult to treat. Therefore, there is an urgent need to develop antimicrobial agents with novel mechanisms of action to combat antibiotic resistance. Quorum sensing (QS) is a crucial mechanism by which bacteria regulate virulence through intercellular signaling. It has become a promising target for adjunctive antibiotic therapy by inhibiting bacterial virulence without affecting growth, thereby generating mild selective pressure and reducing the incidence of drug resistance. LasR, a receptor protein that specifically binds to signaling molecules in the QS system, interferes with its function, modulating the expression of bacterial virulence genes and reducing biofilm maturity.

[0004] Iron is essential for the growth and survival of most bacterial pathogens. Under iron-limiting conditions, bacteria can secrete small molecule metal chelators (such as siderophores) and utilize exogenous siderophores. Siderophores are not only involved in iron transport, but also transport other metals, regulating the production of bacterial virulence factors and biofilm formation. Given the active uptake of siderophores by bacteria in iron-deficient environments, interfering with bacterial iron uptake systems is expected to provide potential opportunities for the development of new antimicrobial agents. Studies have shown that relatively few studies have investigated quorum sensing inhibitors that can interfere with bacterial iron uptake. Summary of the Invention

[0005] In order to address the deficiencies of the prior art, the present invention aims to provide 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives, their preparation methods, and applications. Experiments have shown that such derivatives, as novel quorum sensing inhibitors (QSIs) of Pseudomonas aeruginosa, can not only interfere with bacterial iron uptake, but also have antibacterial sensitization effects.

[0006] In order to achieve the above object, the present invention is implemented through the following technical solutions: In the first aspect, a 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative is a compound represented by formula I;

[0007] Among them, R 1is selected from alkyl, heteroalkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, ; n is an integer from 0 to 6, Y is methylene, O or S, Z is selected from cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, aromatic heteroyl, substituted aromatic heteroyl; A is methylene, sulfonyl or carbonyl.

[0008] In some embodiments, the alkyl group is a linear or branched alkyl group having 1 to 12 carbon atoms, preferably a linear or branched alkyl group having 4 to 8 carbon atoms, and more preferably a linear or branched alkyl group having 5 to 6 carbon atoms.

[0009] The heteroalkyl group described herein refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom (nitrogen, oxygen, sulfur, etc.). In some embodiments, the heteroalkyl group is a linear or branched heteroalkyl group having 1 to 12 carbon atoms. Preferably, the heteroalkyl group is a linear or branched heteroalkyl group having 4 to 8 carbon atoms in which one carbon atom is replaced by nitrogen, oxygen, or sulfur. More preferably, the heteroalkyl group is a linear or branched heteroalkyl group having 5 to 7 carbon atoms in which one carbon atom is replaced by nitrogen, oxygen, or sulfur.

[0010] In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 8 C atoms.

[0011] In some embodiments, the aryl group is selected from phenyl, benzyl, phenethyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, fluorenyl, and acenaphthenyl.

[0012] In some embodiments, the substituted aryl group is an aryl group containing at least one substituent group, wherein the substituent group is an alkyl group, an alkoxy group, a fluoroalkyl group, a halogen group, a nitro group, a hydroxyl group, or a cyano group. Specifically, the alkyl group is a straight-chain or branched alkyl group having 1 to 12 carbon atoms. Specifically, the alkoxy group is a straight-chain or branched alkoxy group having 1 to 12 carbon atoms. Specifically, the fluoroalkyl group is an alkyl group in which at least one hydrogen atom is substituted by a fluorine atom; the fluoroalkyl group is a straight-chain or branched fluoroalkyl group having 1 to 12 carbon atoms. Specifically, the substitution position of the substituent group is the ortho position, the meta position, and / or the para position. Specifically, the substituted aryl group is a substituted phenyl group.

[0013] Wherein, the substituted phenyl group is , R 2 The number of substituents can be one or more, R 2 The substitution sites are ortho, meta and / or para.

[0014] In some embodiments, the aromatic heteroyl group is selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyridinyl, pyrazinyl, furanyl, pyridazinyl, morpholinyl, pyrazolyl, indolyl, pyrimidinyl, benzothiazolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl.

[0015] In some embodiments, the substituted aromatic hetero group is an aromatic hetero group containing at least one substituent. Specifically, the substitution position of the substituent group is ortho, meta and / or para. Specifically, the substituent group is an alkyl group, an alkoxy group, a fluoroalkyl group, a halogen, a nitro group, a hydroxyl group, or a cyano group. Specifically, the alkyl group is a straight-chain or branched alkyl group having 1 to 12 carbon atoms. Specifically, the alkoxy group is a straight-chain or branched alkoxy group having 1 to 12 carbon atoms. Specifically, the fluoroalkyl group is an alkyl group in which at least one hydrogen atom is substituted by a fluorine atom; the fluoroalkyl group is a straight-chain or branched fluoroalkyl group having 1 to 12 carbon atoms.

[0016] In some embodiments, the compound represented by Formula I is selected from the following structures:

[0017] In a second aspect, a method for preparing a 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative comprises the steps of using 1-(4-fluorophenyl)propan-2-one and 2-oxopropionic acid as raw materials to obtain a compound represented by formula I according to the following reaction scheme;

[0018] Among them, R 1 and A and R of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative described in the first aspect of the present invention 1 The same as A, X is halogen.

[0019] In some embodiments, 1-(4-fluorophenyl)propan-2-one (Compound 1) and 2-oxopropionic acid (Compound 2) undergo condensation cyclization reaction to obtain intermediate 3, intermediate 3 reacts with NBS free radical to obtain intermediate 4, intermediate 4 reacts with sodium azide to obtain intermediate 5 by nucleophilic substitution reaction, intermediate 5 is reduced by triphenylphosphine to obtain amino compound 6, amino compound 6 reacts with substituted halide (R 1-AX) condensation to obtain intermediate 7, intermediate 7 is dehydrated to obtain intermediate 8, and intermediate 8 undergoes nucleophilic addition and elimination reactions to obtain the compound shown in formula I.

[0020] Specifically, 1-(4-fluorophenyl)propan-2-one and 2-oxopropionic acid are dissolved in phosphoric acid, heated to 70-80°C for 6-8 hours, and then stirred at room temperature for at least 10 hours. The room temperature refers to the temperature of the indoor environment, generally 15-30°C. Specifically, the purification process is as follows: the precipitated solid is filtered, water is added to the mother liquor, and extracted three times with ethyl acetate. The organic phases are combined, the solvent is evaporated by rotary evaporation, and the residue is purified by column chromatography.

[0021] Specifically, the process of preparing intermediate 4 from intermediate 3 is as follows: dissolving intermediate 3, adding N , N -Azobisisobutyronitrile, heat to 55~65℃ and mix well, then add in batches N -Bromosuccinimide, add after each batch N -bromosuccinimide, raise the temperature to 80-85°C for 1.0-1.5 h, then lower the temperature to 55-65°C; N After the addition of 2-bromosuccinimide is complete, the temperature is raised to 80-85°C and the reaction is continued for 8.5-9.5 hours. After the reaction is complete, the mixture is cooled to room temperature, the solvent is removed, and the mixture is used directly in the next reaction.

[0022] Specifically, the process for preparing intermediate 5 from intermediate 4 is as follows: intermediate 4 is dissolved, sodium azide is added, and the mixture is heated to 80-85°C for 22-26 hours. After completion of the reaction, the reaction solution is cooled to room temperature, water is added, and extraction is performed three times with ethyl acetate. The organic phase is retained and the solvent is evaporated to dryness to obtain a yellow oil, which is used in the next step without further purification.

[0023] Specifically, the process for preparing intermediate 6 from intermediate 5 is as follows: intermediate 5 is added with water and triphenylphosphine, and the reaction is carried out under an inert atmosphere for 15-20 hours. After the reaction is completed, the solvent is evaporated to dryness and the product is purified by column chromatography.

[0024] Specifically, the process of preparing intermediate 7 from intermediate 6 is as follows: dissolving intermediate 6, adding triethylamine and R 1 -AX reacts; when R 1 When A in -AX is a sulfonyl group or a carbonyl group, R 1 -AX is added dropwise and the reaction temperature is room temperature; when R 1 When A in -AX is a methylene group, the reaction temperature is 70-80°C. After the reaction is completed, the solvent is evaporated and the product is purified by column chromatography.

[0025] Specifically, the process for preparing intermediate 8 from intermediate 7 is as follows: intermediate 7 is dissolved, phosphorus pentoxide is added, and the temperature is raised to 60-70°C for reaction for 15-20 hours. After the reaction is completed, the solvent is evaporated and the product is purified by column chromatography.

[0026] Specifically, the process for preparing the compound of Formula I from Intermediate 8 is as follows: Intermediate 8 is dissolved, hydroxylamine hydrochloride and sodium acetate are added, and the reaction is carried out at room temperature for 36-48 hours. After completion of the reaction, the organic solvent is evaporated to dryness, and the product is extracted three times with ethyl acetate. The organic phases are combined, the solvent is evaporated to dryness, and the product is purified by column chromatography.

[0027] In a third aspect, a pharmaceutical composition comprises the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative described in the first aspect of the present invention or its racemate, optical isomer, solvate, or pharmaceutically acceptable salt.

[0028] In some embodiments, the pharmaceutically acceptable salt of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative includes one or more of an inorganic salt and an organic salt. The inorganic salt refers to a salt formed with an inorganic acid, which may be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or the like. The organic salt refers to a salt formed with an organic acid, which may be acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ascorbic acid, or the like.

[0029] In some embodiments, the composition further comprises an antimicrobial active ingredient. The antimicrobial active ingredient refers to a compound other than the compound represented by Formula I of the present invention; the antimicrobial active ingredient may be an antibiotic, such as ciprofloxacin, clarithromycin, tobramycin, azithromycin, norfloxacin, levofloxacin, etc.

[0030] In a fourth aspect, a pharmaceutical preparation comprises an active ingredient and at least one pharmaceutically acceptable excipient, wherein the active ingredient is the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative described in the first aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention.

[0031] The pharmaceutically acceptable excipients described in the present invention refer to excipients that are pharmacologically and / or physiologically compatible with the subject and the active ingredient. In some embodiments, the pharmaceutically acceptable excipients include at least one of a solvent, a disintegrant, a flavoring agent, a preservative, a colorant, a binder, a filler, a stabilizer, an antioxidant, and a lubricant.

[0032] In some embodiments, the dosage form of the pharmaceutical preparation is an injection, tablet, pill, capsule, suspension, emulsion, aerosol, powder, lyophilized powder injection, inclusion compound, implant, patch or ointment.

[0033] In the fifth aspect, a use of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative described in the first aspect of the present invention, the pharmaceutical composition described in the third aspect of the present invention, or the pharmaceutical preparation described in the fourth aspect of the present invention in the preparation of a bacterial quorum sensing inhibitor and / or a bacterial iron chelator.

[0034] The bacterial quorum sensing inhibitor and bacterial iron chelator described in the present invention can be a medicine or a scientific research reagent for use in bacteria-related research.

[0035] In some embodiments, the bacteria are Gram-positive or Gram-negative, preferably Gram-negative, including but not limited to Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Haemophilus influenzae, Shigella, Salmonella, Shigella, Pasteurella, Salmonella typhi, Proteus, Pseudomonas aeruginosa, Bordetella pertussis, Vibrio cholerae, Neisseria meningitidis, Moraxella catarrhalis, and Yersinia, preferably Pseudomonas aeruginosa. Bacterial growth inhibition experiments showed that the aforementioned 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives had no inhibitory effect on the growth and reproduction of Pseudomonas aeruginosa, but effectively reduced its virulence phenotype (including pyocyanin, rhamnolipids, proteases, biofilm, and swarming motility) and interfered with the bacterial QS system and iron uptake system.

[0036] In a sixth aspect, a 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to the first aspect of the present invention, or a pharmaceutical composition according to the third aspect of the present invention, or a pharmaceutical preparation according to the fourth aspect of the present invention, is used in the preparation of an antibacterial sensitizer. Experiments using the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative in combination with antibacterial drugs have shown that the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative can increase the sensitivity of drug-resistant bacteria to antibiotics, thereby enhancing the efficacy of the drugs.

[0037] In the seventh aspect, a 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative described in the first aspect of the present invention, or the pharmaceutical composition described in the third aspect of the present invention, or the pharmaceutical preparation described in the fourth aspect of the present invention is used in the preparation of a drug for preventing and / or treating diseases caused by bacterial infection.

[0038] In some embodiments, the disease caused by bacterial infection includes but is not limited to pneumonia, cystic fibrosis, urinary tract infection, sepsis, endocarditis, peritonitis, cholecystitis, cystitis, diarrhea, gastroenteritis, etc.

[0039] The beneficial effects of the present invention are: (1) The 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives of the present invention inhibit the virulence of bacteria without affecting their growth activity, thereby generating mild selective pressure and reducing the incidence of drug resistance.

[0040] (2) The 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives of the present invention interfere with the QS system and iron uptake system of Pseudomonas aeruginosa in a concentration-dependent manner, thereby inhibiting its virulence phenotype.

[0041] (3) The 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives of the present invention have good antibacterial synergistic effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0043] Figure 1 This is a graph showing the results of investigating the inhibitory activity of compounds I-1 to I-19 against pyocyanin in Pseudomonas aeruginosa PAO1 in the examples of the present invention; Figure 2 This is a graph showing the results of investigating the inhibitory activity of compounds I-20 to I-27 against pyocyanin in Pseudomonas aeruginosa PAO1 in the examples of the present invention; Figure 3 This is a graph showing the results of investigating the inhibitory activity of compounds I-28 to I-35 against pyocyanin in Pseudomonas aeruginosa PAO1 in the examples of the present invention; Figure 4 Graph showing the results of the investigation of the inhibitory activity of compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 against Pseudomonas aeruginosa PAO1 protease in the examples of the present invention; Figure 5 Graph showing the results of investigation of the inhibitory activity of rhamnolipids against Pseudomonas aeruginosa PAO1 of compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 in the examples of the present invention; Figure 6 Graph showing the results of the investigation of the inhibitory activity of compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 against the biofilm formation of Pseudomonas aeruginosa PAO1 in the examples of the present invention; Figure 71-12, 1-16, 1-17, 1-18, 1-19, 1-25, 1-26, 1-29 and 1-32 of the present invention and the antibacterial agent ciprofloxacin or clarithromycin, A is the synergistic anti-Pseudomonas aeruginosa 27853 effect with clarithromycin, B is the synergistic anti-resuscitation Pseudomonas aeruginosa 27853 effect with ciprofloxacin, C is the synergistic anti-Pseudomonas aeruginosa PAO1 effect with clarithromycin, and D is the synergistic anti-Pseudomonas aeruginosa PAO1 effect with ciprofloxacin; Figure 8 The effect of compound I-17 on PAO1- lasB-gfp (A), PAO1- rhlA-gfp (B), PAO1- pqsA-gfp (C) and PAO1- gfp (D) Graph showing the results of the inhibitory activity study; Figure 9 This is a graph showing the results of investigating the effects of compound I-17 on the fluorescence levels of Pyoverdine (Pvd) (A) and Pyochelin (Pch) (B) in an example of the present invention. DETAILED DESCRIPTION

[0044] In order 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.

[0045] Example 1 Synthesis of I-1 to I-27 (1) Synthesis of intermediate 3

[0046] 1-(4-Fluorophenyl)propan-2-one (Compound 1, 67.0 mmol) and 2-oxopropionic acid (Compound 2, 168.0 mmol) were dissolved in 200 mL of phosphoric acid and reacted at 75°C for 7 h. The reaction was monitored by TLC, followed by stirring at room temperature overnight. The next day, the precipitated solid was filtered, and 200 mL of water was added to the mother liquor. The product was extracted three times with 400 mL of ethyl acetate. The organic phases were combined, the solvent was evaporated to dryness, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1).

[0047] (2) Synthesis of intermediate 4

[0048] Intermediate 3 (54.0 mmol) was dissolved in 60 mL of acetonitrile and added N , N -azobisisobutyronitrile (5.0 mmol), heated to 60 °C and stirred for 30 min. Add three timesN After each addition, heat the temperature to 80°C, then cool to 60°C after 1 h before adding again. After complete addition, react at 80°C for 9 h. Monitor the reaction by TLC. After completion, cool the reaction mixture to room temperature and evaporate the solvent to dryness, yielding a yellow solid that was used in the next step without further purification.

[0049] (3) Synthesis of intermediate 5

[0050] Intermediate 4 (10.0 mmol) was dissolved in 15 mL of a 4:1 DMF-water mixture. Sodium azide (16.0 mmol) was added and the temperature was gradually raised from room temperature to 80°C for 24 h. The reaction was monitored by TLC. After completion, the reaction solution was cooled to room temperature, 45 mL of water was added, and the mixture was extracted three times with 60 mL of ethyl acetate. The organic phase was retained and the solvent was evaporated to dryness to obtain a yellow oil, which was used in the next step without further purification.

[0051] (4) Synthesis of intermediate 6

[0052] Intermediate 5 (31.0 mmol) was dissolved in 100 mL of tetrahydrofuran, and water (50.0 mmol) and triphenylphosphine (50.0 mmol) were added. Under nitrogen, the reaction was allowed to react at room temperature for 18 h, monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness, and the product was purified by column chromatography (dichloromethane:methanol = 100:1) to obtain Intermediate 6.

[0053] (5) Synthesis of intermediate 7

[0054] When synthesizing intermediate 7 in place of an amide or sulfonamide, dissolve intermediate 6 (11.7 mmol) in 40 mL of dichloromethane, add triethylamine (35.0 mmol), and stir at 0°C. Add a solution of octanoyl chloride (11.7 mmol) diluted in dichloromethane dropwise. After 1 hour, bring the mixture to room temperature and stir. Monitor the reaction by TLC. After completion of the reaction, evaporate the solvent to dryness, and purify by column chromatography (dichloromethane:methanol = 200:1) to obtain intermediate 7.

[0055] (6) Synthesis of intermediate 8

[0056] Intermediate 7 (5.1 mmol) was dissolved in 17 mL of chloroform, and phosphorus pentoxide (51.2 mmol) was added. The temperature was raised to 65°C and the reaction was allowed to react for 18 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness, and the product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain Intermediate 8.

[0057] (7) Synthesis of compound I-17

[0058] Intermediate 8 (4.0 mmol) was dissolved in a mixture of 15 mL of ethanol and 15 mL of water. 3 mL of dichloromethane was added for solubilization and stirred at room temperature. Hydroxylamine hydrochloride (40.0 mmol) and sodium acetate (40.0 mmol) were added to the reaction mixture and allowed to react at room temperature for 40 h. The reaction was monitored by TLC. After completion of the reaction, the organic solvent was evaporated to dryness, and the product was extracted three times with 30 mL of ethyl acetate. The organic phases were combined, the solvent was evaporated to dryness, and the product was purified by column chromatography (dichloromethane:methanol = 60:1) to obtain the target compound I-17.

[0059] The characterization information of the compounds is shown in Table 1.

[0060] Compounds I-1 to I-27 were prepared according to the method of Example 1, except that the starting materials were replaced accordingly.

[0061] Example 2 Compounds I-28 to I-35 Synthetic intermediate 7

[0062] When synthesizing secondary amine-substituted intermediate 7, intermediate 6 (11.7 mmol) was dissolved in 40 mL N , N To the mixture of 1,4-dimethylformamide, triethylamine (35.0 mmol) and substituted benzyl chloride (11.7 mmol) were added, and the temperature was raised to 75°C with stirring. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness and the product was purified by column chromatography (dichloromethane:methanol = 200:1) to obtain intermediate 7.

[0063] The subsequent steps were the same as in Example 1 to obtain compound I-29.

[0064] The characterization information of the compounds is shown in Table 1.

[0065] Compounds I-28 to I-35 were prepared according to the method of Example 2, except that the starting materials were replaced accordingly.

[0066] Table 1 Characterization information of compounds I-1 to I-35

[0067] Example 3 Antibacterial activity detection This example tests the activity of target compounds (i.e. compounds I-1 to I-25, II-1 to II-6 of the present invention) against various Gram-positive bacteria, including Bacillus subtilis ( B. subtilis ATCC 9372), Bacillus pumilus ( B. pumilus CMCC63202), sensitive Staphylococcus aureus ( S. aureus ATCC25923), methicillin-resistant Staphylococcus aureus ( S. aureus ATCC43300) and Gram-negative bacteria, including Pseudomonas aeruginosa ( P. aeruginosa ATCC27853), Escherichia coli ( E. coli ATCC25922), Pseudomonas aeruginosa ( P. aeruginosa The minimum inhibitory concentration (MIC) of PAO1 is used to characterize the antibacterial potency of the compounds of this invention. The strains used were obtained from the China General Microbiology Culture Collection (CGMCC), the China Industrial Microbiology Culture Collection (CICC), and clinical isolates from Qilu Hospital.

[0068] The MICs of compounds I-1–I-35, as well as ciprofloxacin (CIP), clarithromycin (CLA), and azithromycin (AZM) were determined using the two-fold slurry dilution method. Based on the MIC results, compounds lacking antimicrobial activity were screened out. Reference substances (ciprofloxacin (CIP), clarithromycin (CLA), and azithromycin (AZM) were purchased from Anaiji Chemical. Based on these results, the antimicrobial activities of the target compounds were determined, as shown in Table 2.

[0069] Table 2 Minimum inhibitory concentrations of compounds I-1 to I-35 against various strains

[0070] a B. subtilis ATCC9372: Bacillus subtilis ATCC9372, penicillin-susceptible strain; b B. pumilus CMCC63202: Bacillus pumilus CMCC63202, penicillin-susceptible strain; c S. aureus ATCC25923: Staphylococcus aureus ATCC25923, erythromycin-susceptible strain; d S. aureus ATCC43300: Staphylococcus aureus ATCC43300, methicillin-resistant strain; e P. aeruginosa PAO1: Pseudomonas aeruginosa CGMCC 1.12483, wild typestrain; f E. coli ATCC25922: Escherichia coli ATCC2592, penicillin-susceptiblestrain; g P. aeruginosa ATCC27853: Pseudomonas aeruginosa ATCC27853, penicillin-susceptible strain, not characterized. A CIP: ciprofloxacin; B CLA: clarithromycin; C AZM: azithromycin. From the above experimental results, it can be seen that the 35 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives of the present invention are effective against a variety of Gram-positive bacteria, including Bacillus subtilis ( B. subtilis ATCC 9372), Bacillus pumilus ( B. pumilus CMCC63202), sensitive Staphylococcus aureus ( S. aureus ATCC25923), methicillin-resistant Staphylococcus aureus ( S. aureus ATCC43300) and Gram-negative bacteria, including Pseudomonas aeruginosa ( P. aeruginosa ATCC27853), Escherichia coli ( E. coli ATCC25922), Pseudomonas aeruginosa ( P. aeruginosa PAO1) All tested strains had no antibacterial activity, which met the prerequisite for the development of QSIs.

[0071] Example 4 Effects of the above derivatives on the expression of pyocyanin in Pseudomonas aeruginosa PAO1 This example measures the activity of target compounds (i.e. compounds I-1 to I-35 of the present invention) against Pseudomonas aeruginosa ( P. aeruginosa The effect of pyocyanin expression on PAO1 was used to characterize the QS inhibitory effect of the compounds of the present invention. The strains used were obtained from the China General Microbiological Culture Collection Center (CGMCC).

[0072] Experimental method: Pseudomonas aeruginosa PAO1 was revived and subcultured into LB broth, which was then cultured in a 37 °C constant temperature biochemical incubator for 20 h. The subcultured PAO1 was diluted with LB broth to an OD 620 = 0.05, and the diluted bacterial solution was cultured to the logarithmic growth phase. The bacterial solution in the logarithmic growth phase was diluted again with LB broth to OD 620 = 0.05. Then use a pipette to draw 5 mL into a 10 mL ep tube, add 50 μL of the test compound and control drug stock solution to a final concentration of 128 μg / mL respectively, and set up a negative control group and a blank control group at the same time, and mark them. Make four parallel groups for each sample and culture them in a shaking incubator at 37 °C and 200 rpm for 18 h. Use a low-temperature high-speed centrifuge to centrifuge at 10,000 rpm for 10 min, pour the supernatant into a new ep tube, and extract the supernatant with 3 mL of chloroform. After standing and separating the layers, discard the aqueous layer. Then use 1 mL of 0.2 M hydrochloric acid to back-extract the chloroform layer. After standing and separating the layers, take the hydrochloric acid layer solution in a 96-well plate and measure the OD 492 The inhibition rate of pyocyanin was 1-(Abs sample -Abs blank ) / (Abs negative -Abs blank ) × 100%.

[0073] Depend on Figure 1 It can be seen that 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives (I-1 to I-19) exhibited strong pyocyanin inhibitory activity. Compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, and I-19 significantly reduced pyocyanin production by approximately 50%. Compound I-18, in particular, exhibited the strongest inhibition, reaching 56.67%. Compound I-4, which had the lowest inhibition rate, also exhibited pyocyanin expression levels of approximately 70%.

[0074] Depend on Figure 2The results show that 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives (I-20 to I-27) exhibit moderate inhibitory activity against pyocyanin. Among them, compounds I-25 and I-26 exhibited strong pyocyanin inhibitory activity, with expression levels reaching 50.74% and 45.5% of the negative control, respectively.

[0075] Depend on Figure 3 It was found that among the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivatives (I-28 to I-35), the most effective compound was I-32, with an inhibition rate against pyocyanin of 57.35%. Compound I-29 had a pyocyanin inhibition rate close to that of I-32, at 46.32%.

[0076] Example 5 Effects of derivatives I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 on the expression of Pseudomonas aeruginosa PAO1 protease This example was conducted by determining the activity of target compounds (i.e., compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29, and I-32 of the present invention) against Pseudomonas aeruginosa ( P. aeruginosa The effect of PAO1 protease expression on the QS inhibitory effect of the compound of the present invention was characterized. The strains used were obtained from the China General Microbiological Culture Collection Center (CGMCC).

[0077] Experimental method: Pseudomonas aeruginosa PAO1 was revived and subcultured into LB broth, which was then cultured in a 37 °C constant temperature biochemical incubator for 20 h. The subcultured PAO1 was diluted with LB broth to an OD 620 = 0.05, and the diluted bacterial solution was cultured to the logarithmic growth phase. The bacterial solution in the logarithmic growth phase was diluted again with LB broth to OD 620= 0.05. Then use a pipette to draw 5 mL into a 10 mL ep tube, add 50 μL of the test compound and control drug stock solution to a final concentration of 128 μg / mL respectively, and set up a negative control group and a blank control group at the same time, and mark them. Make three parallel groups for each sample and culture them in a 37 °C, 200 rpm shaking incubator for 18 h. After the incubation, centrifuge for 10 min at a speed of 10,000 rpm in a low-temperature high-speed centrifuge, draw 150 μL of supernatant and add it to a 2 mL ep tube, and then take 250 μL of azocasein-Tris-HCl (2% (w / v)) solution and add it. After mixing, put the ep tube into a 4 °C refrigerator for reaction for 8 h. After the reaction is completed, add 1.2 mL of 10% trichloroacetic acid solution to the ep tube to terminate the reaction, and then centrifuge the ep tube at 10,000 rpm for 5 min, take the supernatant in a 96-well plate, and measure the OD 450 The inhibition rate of protease was 1-(Abs sample -Abs blank ) / (Abs negative -Abs blank ) × 100%.

[0078] Depend on Figure 4 As shown, among compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29, and I-32, compounds I-25, I-26, and I-32 exhibited moderate inhibitory activity against proteases, even outperforming the positive control. Protease activity in samples treated with compounds I-25, I-26, and I-32 was only 77.80%, 78.19%, and 78.39% of that in the negative control, respectively, while the expression level of the positive control, C30-1 (bromofuranone), was 84.48%. Compounds I-19 and I-29 exhibited comparable inhibition rates against proteases as C30-1, both around 16%.

[0079] Example 6 Effects of derivatives I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 on rhamnolipid expression in Pseudomonas aeruginosa PAO1 This example was conducted by determining the activity of target compounds (i.e., compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29, and I-32 of the present invention) against Pseudomonas aeruginosa ( P. aeruginosa The effects of rhamnolipid expression on PAO1 (PAO1) were used to characterize the QS inhibitory effect of the compounds of the present invention. The strains used were obtained from the China General Microbiological Culture Collection Center (CGMCC).

[0080] Experimental method: Pseudomonas aeruginosa PAO1 was revived, subcultured into sugar-free medium, and cultured in a 37 °C constant temperature biochemical incubator for 20 h. The OD 620 = approximately 1.0. Dilute the bacterial suspension with sugar-free medium at a ratio of 3:100. Pipette 3 mL of the diluted suspension into a 5 mL Eppendorf tube. Add 30 μL of the test compound and control drug stock solutions to a final concentration of 128 μg / mL. Set up negative and blank controls, labeling them. Each sample is replicated in triplicate and incubated in a shaking incubator at 37°C, 200 rpm for 48 hours. Centrifuge at 10,000 rpm for 10 minutes in a low-temperature high-speed centrifuge. Pipette 250 μL of the supernatant into a 2 mL Eppendorf tube. Extract twice with 500 μL of ethyl acetate. Combine the two ethyl acetate layers into a new Eppendorf tube and allow to evaporate overnight in a ventilated, dry place. Add 100 μL of deionized water to the Eppendorf tube to dissolve the residue. Add 900 μL of freshly prepared orcinol-concentrated sulfuric acid reagent, vortex, and heat the Eppendorf tube in an 80°C water bath for 30 minutes to yield an orange-yellow solution. After cooling to room temperature, the solution was placed in a 96-well plate and OD421 was measured. The inhibition rate of rhamnolipid was 1-(Abs sample -Abs blank ) / (Abs negative -Abs blank ) × 100%.

[0081] Depend on Figure 5 It can be seen that among compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32, the inhibitory effect of compound I-11 on rhamnolipid production at a concentration of 102.4 μg / mL was comparable to that of the positive control C10 (C10-CPA, N The inhibitory effects of all compounds on rhamnolipid production were lower than that of C10, and compounds I-7 and I-12 had no significant inhibitory effect on rhamnolipid production.

[0082] Example 7 Effects of derivatives I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 on biofilm formation of Pseudomonas aeruginosa PAO1 In this example, the target compounds (I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32) were tested for their effects on Pseudomonas aeruginosa ( P. aeruginosa The effects of the compounds on PAO1 biofilm formation were used to characterize the QS inhibitory effect of the compounds. The strains used were obtained from the China General Microbiological Culture Collection Center (CGMCC).

[0083] Experimental method: Pseudomonas aeruginosa PAO1 was revived and subcultured into LB broth, which was then cultured in a 37 °C constant temperature biochemical incubator for 20 h. The subcultured PAO1 was diluted with LB broth to an OD 620 = 0.05, and the diluted bacterial solution was cultured to the logarithmic growth phase. The bacterial solution in the logarithmic growth phase was diluted again with LB broth to OD 620 = 0.05. Add the appropriate amount of the above bacterial solution and the stock solution of the test compound to a 96-well plate and dilute it two-fold to 32 μg / mL, resulting in 100 μL per well. Each sample was run in triplicate, with negative and blank controls set up. Seal the perimeter of the experimental wells with 200 μL of broth to prevent edge effects. Incubate in a 37°C biochemical incubator for 18 h. Discard the liquid from the wells, avoiding contact with the sides and bottom to prevent damage to the biofilm and affect experimental results. Wash three times with 150 μL of PBS buffer, then add 150 μL of anhydrous methanol and leave for 15 minutes to fix the biofilm. Discard the methanol and dry the plate in a 30°C oven. Add 150 μL of 0.1% crystal violet solution and leave for 15 minutes to stain the biofilm. Discard the stain and repeatedly rinse the 96-well plate with purified water until the rinse water is colorless. Dry the plate. Finally, 150 μL of 33% glacial acetic acid solution was added to a 96-well plate and shaken for 5-10 min. After the biofilm was completely dissolved, the OD was measured. 570 The biofilm formation inhibition rate was 1-(Abs sample -Abs blank ) / (Abs negative -Abs blank ) × 100%.

[0084] Depend on Figure 6It can be seen that among compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29, and I-32, compound I-17 had a greater inhibitory effect on biofilm formation than AZM. After the bacteria were treated with compound I-17, the residual biofilm was only 38.60%. Compound I-18 showed activity similar to that of AZM, with a residual biofilm of 47.83%. Although these compounds all had some inhibitory effect on the virulence factors tested, compounds I-11 and I-12 showed only weak biofilm inhibition ability, while compounds I-5, I-7, I-10, I-16, and I-19 had no significant inhibitory effect on biofilm formation. SAR showed that straight-chain alkanes, as hydrophobic groups, had stronger inhibitory activity against biofilms, and the activity gradually increased with increasing chain length.

[0085] Example 8 Synergistic antibacterial effect of derivatives I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 with antibacterial agents Experimental Methods: Resuscitate Pseudomonas aeruginosa 27853 and Pseudomonas aeruginosa PAO1 and streak inoculate onto solid culture medium. Incubate the culture medium in a 37°C incubator for 20 hours. Add 6-8 mL of normal saline to a turbidimetric tube. Use an inoculating loop to collect a healthy subculture colony and mix it into the turbidimetric tube until the concentration reaches 1.5 × 10 8 CFU / mL. Take 2 mL of bacterial suspension and add 18 mL of normal saline to obtain bacterial solution. Take a sterile 96-well plate, add 187.5 µL of liquid culture medium to the second column, and add 95 µL of liquid culture medium to columns 3-6; add 10 µL of antibiotic stock solution to column 2, and add 5 µL of antibiotic stock solution to columns 3-6; add 2.5 µL of the compound to be tested to column 2 until the compound concentration is 128 μg / mL; mix the culture medium and compound in column 2, and take 100 µL to add to the next column, mix, and mix in sequence to column 5. Discard the extra 100 µL. At this time, the volume of each column is 100 µL, and the drug concentration decreases by two times from 128 to 16 μg / mL from columns 2-5, respectively. The antibiotic concentration is 0.4 μg / mL ciprofloxacin or 3.2μg / mL clarithromycin; add 5 µL of bacterial solution to columns 2-6, and set up a negative control (culture medium + DMSO + bacterial solution) for each group, and use 200 µL around it. The LB culture medium was sealed to prevent edge effects and serve as a blank control. Three parallel experiments were performed for each sample. The 96-well plate was placed in a 37°C constant temperature incubator for 20 h. After the incubation, the plate was shaken for 30 s in a microplate reader and the optical density (OD) was read. 620 ) Calculate bacterial mortality: 1-(Abs sample-Abs blank ) / (Abs negative -Abs blank ) × 100%.

[0086] Depend on Figure 7 It can be seen that different concentrations of compounds I-5, I-7, I-10, I-11, I-12, I-16, I-17, I-18, I-19, I-25, I-26, I-29 and I-32 combined with ciprofloxacin or clarithromycin are more effective in inhibiting bacterial viability than the same concentration of antibiotics alone.

[0087] Example 9 Derivative I-17 for GFP reporter strain PAO1- lasB-gfp , PAO1- rhlA-gfp , PAO1- pqsA-gfp and PAO1- gfp Inhibitory activity In this example, the target compound I-17 was tested for its effect on the GFP reporter strain PAO1- lasB-gfp , PAO1- rhlA- gfp , PAO1- pqsA-gfp and PAO1- gfp The inhibitory activity characterizes the targeting activity of the compounds of the present invention on the quorum sensing system.

[0088] Experimental method: The test compound I-2 was diluted to 32, 16, 8 and 4 μg / mL in a 96-well plate by two-fold dilution method. 75 μL of liquid culture medium containing different concentrations of the compound and 75 μL of overnight culture were added to the 96-well plate and diluted to OD 600 The 96-well plate was placed in a multi-mode microplate detection system, and the temperature was set to 37 °C, the excitation wavelength was 485 nm, and the emission wavelength was 528 nm. The fluorescence intensity and OD were measured every 15 min. 600 , the measurement was continued for 10 hours, and the effect of the compound on the three QS pathways was determined by calculating the ratio of fluorescence intensity to absorbance.

[0089] Depend on Figure 8 It can be seen that compound I-17 can inhibit PAO1- lasB-gfp and PAO1- pqsA- gfp Fluorescence expression, but did not affect PAO1- gfp The fluorescence of alas and pqsThe results of this experiment more directly demonstrated the targeting of our newly synthesized compounds to the quorum sensing system rather than directly acting on green fluorescent protein, indicating that our newly synthesized compounds can be effectively used as QSIs for the treatment of bacterial infections.

[0090] Example 10 Effect of derivative I-17 on Pvd and Pch fluorescence levels This example characterizes the targeting of the compound of the present invention to the iron uptake system by measuring the effect of the target compound I-17 on the fluorescence levels of Pvd and Pch.

[0091] Experimental method: Using the two-fold dilution method, the compound was diluted with culture medium in a black transparent bottom 96-well plate to a concentration twice the preset concentration and mixed. At the same time, a negative control group (DMSO + culture medium + bacterial solution) and a blank control group (culture medium) were set up, and three parallel experiments were set up for each sample. Subsequently, an equal volume of the above bacterial solution as the compound was added to the 96-well plate, and 200 μL of culture medium was added to the periphery. The plate was placed in a multi-function microplate reader, set at 37°C, incubated and read, including optical density (OD 600 ), Pvd fluorescence (excitation wavelength: 400 nm, emission wavelength: 447 nm), and Pch fluorescence (excitation wavelength: 350 nm, emission wavelength: 430 nm). Calculate the ratio of fluorescence intensity to absorbance.

[0092] Depend on Figure 9 Compound I-17 significantly increased Pvd and Pch levels in a concentration-dependent manner, counteracting the iron-deficient environment of the culture medium, while its corresponding intermediate 7 had only a slight effect on Pvd and Pch production. These results suggest that the introduction of the hydroxamic acid structure imparts compound I-17 with a high affinity for iron.

[0093] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative, characterized in that: It is a compound represented by formula I; Among them, R 1 is selected from alkyl, heteroalkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, ; n is an integer from 0 to 6, Y is methylene, O or S, Z is selected from cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, aromatic heteroyl, substituted aromatic heteroyl; A is methylene, sulfonyl or carbonyl.

2. The 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to claim 1, characterized in that: The alkyl group is a straight or branched chain alkyl group with 1 to 12 carbon atoms; Or, the heteroalkyl group is a straight or branched heteroalkyl group having 1 to 12 carbon atoms; Or, the cycloalkyl group is a cycloalkyl group having 3 to 8 C atoms; or, the aryl group is selected from phenyl, benzyl, phenethyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, fluorenyl and acenaphthenyl; Alternatively, the substituted aryl group is an aryl group containing at least one substituent group, wherein the substituent group is an alkyl group, an alkoxy group, a fluoroalkyl group, a halogen group, a nitro group, a hydroxyl group, or a cyano group; Or, the substituted aryl is a substituted phenyl or, the aromatic heterogroup is selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyridinyl, pyrazinyl, furanyl, pyridazinyl, morpholinyl, pyrazolyl, indolyl, pyrimidinyl, benzothiazolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl; Alternatively, the substituted aromatic hetero group is an aromatic hetero group containing at least one substituent group; the substituent group is an alkyl group, an alkoxy group, a fluoroalkyl group, a halogen group, a nitro group, a hydroxyl group, or a cyano group.

3. The 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to claim 1, characterized in that: The compound represented by formula I is selected from the following structures:

4. A method for preparing a 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative, characterized in that: The method comprises the steps of using 1-(4-fluorophenyl)propan-2-one and 2-oxopropionic acid as raw materials to obtain the compound represented by formula I according to the following reaction scheme; Among them, R 1 and A and R of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to claim 1 1 The same as A, X is halogen.

5. A pharmaceutical composition, characterized in that: The invention comprises the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to any one of claims 1 to 3 or its racemate, optical isomer, solvate, and pharmaceutically acceptable salt.

6. The pharmaceutical composition according to claim 5, characterized in that The invention also includes an antibacterial active ingredient; the antibacterial active ingredient is ciprofloxacin, clarithromycin, tobramycin, azithromycin, norfloxacin or levofloxacin.

7. A pharmaceutical preparation comprising an active ingredient and at least one pharmaceutically acceptable excipient, wherein the active ingredient is the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 6 or 7; Preferably, the pharmaceutically acceptable excipients include at least one of a solvent, a disintegrant, a flavoring agent, a preservative, a colorant, a binder, a filler, a stabilizer, an antioxidant, and a lubricant; Preferably, the dosage form of the pharmaceutical preparation is an injection, tablet, pill, capsule, suspension, emulsion, aerosol, powder, lyophilized powder injection, inclusion compound, landfill, patch or liniment.

8. Use of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to any one of claims 1 to 3, or 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 and / or a bacterial iron chelator. Preferably, the bacteria are Gram-positive bacteria or Gram-negative bacteria, preferably Gram-negative bacteria; the Gram-negative bacteria include but are not limited to Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Haemophilus influenzae, Shigella, Salmonella, Shigella, Pasteurella, Salmonella typhi, Proteus, Pseudomonas aeruginosa, Bordetella pertussis, Vibrio cholerae, Neisseria meningitidis, Catarrhalis and Yersinia, preferably Pseudomonas aeruginosa.

9. Use of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to any one of claims 1 to 3, the pharmaceutical composition according to claim 6 or 7, or the pharmaceutical preparation according to claim 7 in the preparation of an antibacterial sensitizer.

10. Use of the 4-(4-fluorophenyl)-1,5-dihydroxy-5-methylpyrrolidone derivative according to any one of claims 1 to 3, or the pharmaceutical composition according to claim 6 or 7, or the pharmaceutical preparation according to claim 7 in the preparation of a medicament for preventing and / or treating diseases caused by bacterial infection; Preferably, the disease caused by bacterial infection includes one or more of pneumonia, cystic fibrosis, urinary tract infection, sepsis, endocarditis, peritonitis, cholecystitis, cystitis, diarrhea, and gastroenteritis.

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