A 1,3,4-thiadiazole peptide deformylase enzyme inhibitor and preparation and application thereof

Abstract

This invention relates to a 1,3,4-thiadiazole peptide deformylase inhibitor and its preparation and application. The structural formula is shown in formula (1): wherein, R 1 It is n-butyl or cyclopentylmethyl; R 2 The compounds are hydrogen-containing, straight-chain alkanes, cyclic alkanes, aromatic rings, substituted biphenyls, or heterocyclic rings. The 1,3,4-thiadiazole peptide deformylase inhibitors provided by this invention can effectively inhibit bacterial protein synthesis, thereby achieving sterilization. These compounds exhibit excellent inhibitory activity against Gram-positive drug-resistant bacteria, especially the clinically challenging methicillin-resistant Staphylococcus aureus (MRSA). In particular, some preferred compounds show inhibitory activity 4-8 times that of the control standards vancomycin and linezolid. The 1,3,4-thiadiazole peptide deformylase inhibitors provided by this invention also exhibit inhibitory activity against Gram-negative drug-resistant bacteria, especially against drug-resistant Acinetobacter baumannii, known as "superbugs," with an inhibitory activity reaching 0.5 μg / mL, far superior to vancomycin and linezolid.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and in particular relates to a 1,3,4-thiadiazole peptide deformylase inhibitor and its preparation and application. Background Technology

[0002] Diseases caused by microbial infections, such as plague, tuberculosis, and cholera, have historically caused enormous population declines. It wasn't until the advent of antibiotics that humanity truly gained the upper hand in the fight against bacteria. Penicillin was the first antibiotic discovered and used clinically to treat patients with bacterial infections. Over time, more and more antibiotics have been discovered and used to treat patients with bacterial infectious diseases.

[0003] However, while humans use antibiotics to combat bacteria, bacteria have also evolved resistance. Studies have shown that bacteria primarily utilize two genetic strategies to defend against antibiotics: 1. Gene mutation, usually related to the mechanism of action of antimicrobial compounds. As the results of each gene mutation accumulate during bacterial evolution, bacteria acquire various resistance genes, also known as "natural resistance"; 2. Acquired resistance, which involves acquiring exogenous DNA encoding resistance determinants through horizontal gene transfer. Acquired resistance allows resistance genes to transfer between strains, leading to multidrug resistance, such as the NDM-1 super-resistant Enterobacterium that emerged in India. Therefore, the increasing prevalence of antimicrobial resistance (AMR) infections has become a new challenge in anti-infective therapy in the new century and a major threat to human health and life worldwide.

[0004] Most existing antibiotics inhibit three key aspects of the bacterial growth cycle: bacterial cell wall synthesis, ribosomal protein synthesis, and DNA replication. Designing novel antibiotics that target the same set of targets to combat drug-resistant bacteria is becoming increasingly difficult. Therefore, in the face of bacterial resistance, we urgently need to find new antibacterial targets and develop antibacterial drugs with mechanisms of action against multidrug resistance.

[0005] Peptide deformylase (PDF) is a ferrous ion-containing enzyme. 2+Metalloproteinases, widely present in bacteria, play a crucial role in prokaryotic protein synthesis. The start codon encodes formylmethionine, which, under the catalysis of formylase, is converted from methionine-tRNAf (Met-RNAfMet) to formylmethionine-tRNAf (Formyl-Met-RNAfMet), thus participating in the initiation stage of prokaryotic peptide chain synthesis. Meanwhile, tRNAm carries ordinary methionine and participates in peptide chain synthesis. Through peptide chain elongation, termination, and release, nascent polypeptides are obtained. Not all nascent polypeptides possess biological activity; they require processing and modification to become mature proteins. Nascent polypeptides, catalyzed by peptide deformylases, lose their N-terminal formyl group, and then methionine aminopeptidase (MAP) removes methionine residues to ultimately synthesize active proteins. Therefore, inhibiting peptide deformylases, halting protein synthesis at the N-terminal formyl group removal stage, can effectively inhibit bacterial growth. Currently, there is relatively more research on peptide deformylases as antibacterial targets, and four drugs (peptide deformylase inhibitors) have entered the clinical stage, namely compounds BB83698, LBM415, GSK1322322, and IDP-73152, with the following structures:

[0006]

[0007] However, current PDF inhibitors under development share a common problem: peptide-based PDF inhibitors produce strong oxidative metabolites during human metabolism, leading to methemoglobinemia. Another drawback of PDF inhibitors is their narrow antibacterial spectrum. Although PDFs are widely present in bacteria, due to differences in bacterial structure, most currently developed PDF inhibitors are only effective against Gram-positive bacteria, with almost no inhibitory effect on Gram-negative bacteria. Summary of the Invention

[0008] Based on the existing problems that existing peptide-like PDF inhibitors produce strong oxidative metabolites during human metabolism, causing methemoglobinemia, and that most PDF inhibitors are only effective against Gram-positive bacteria and have almost no inhibitory effect on Gram-negative bacteria, this invention provides a 1,3,4-thiadiazole peptide deformylase inhibitor and its preparation and application.

[0009] This invention addresses a common problem among investigational PDF inhibitors (peptide-based PDF inhibitors produce strong oxidative metabolites during human metabolism, leading to methemoglobinemia). The reason may be that after drugs containing amide bonds enter the human body, they are first hydrolyzed into phenylamine derivatives. After being metabolized by enzymes in the liver, they produce N-phenylhydroxylamine. A small amount of N-phenylhydroxylamine can oxidize a large amount of hemoglobin into methemoglobin, reducing the number of hemoglobins in the blood, causing a decrease in blood oxygen concentration, and resulting in hypoxia symptoms.

[0010] To avoid the adverse reaction of methemoglobinemia, the structure of PDF inhibitors should be optimized to reduce the number of amide bonds in the compound and avoid or significantly reduce the production of N-phenylhydroxylamine.

[0011] The 1,3,4-thiadiazole peptide deformylase inhibitor provided by this invention is a novel antibacterial drug containing 1,3,4-thiadiazole. This class of drugs can effectively kill bacteria resistant to existing antibiotics. Unlike existing PDF inhibitors that can only kill Gram-positive bacteria, the preferred compounds of the 1,3,4-thiadiazole PDF inhibitor provided by this invention have good killing ability against both drug-resistant Gram-positive and Gram-negative bacteria. In addition, by using 1,3,4-thiadiazole to replace the amide bond in the original peptide-like PDF inhibitor, the use of aniline building blocks can be avoided, thereby effectively reducing or avoiding the formation of N-phenylhydroxylamine in metabolites and reducing the formation of methemoglobinemia.

[0012] The objective of this invention can be achieved through the following technical solutions:

[0013] This invention first provides a 1,3,4-thiadiazole peptide deformylase inhibitor, the structural formula of which is shown in formula (1):

[0014]

[0015] Among them, R 1 It is n-butyl or cyclopentylmethyl; R 2 It can be hydrogen, straight-chain alkanes, cyclic alkanes, aromatic rings, substituted biphenyls, or heterocyclic rings.

[0016] In one embodiment of the present invention, R 2 The cyclic alkane group is selected from one of the following structures:

[0017]

[0018] In one embodiment of the present invention, R 2 The straight-chain alkanes of the group are selected from

[0019] In one embodiment of the present invention, R 2 The aromatic ring of the group is selected from one of the following structures:

[0020]

[0021] In one embodiment of the present invention, R 2 The heterocycle of the group is selected from one of the following structures:

[0022]

[0023] In one embodiment of the present invention, the 1,3,4-thiadiazole peptide deformylase inhibitor is selected from one of the following structures:

[0024]

[0025] The present invention further provides a method for preparing the 1,3,4-thiadiazole peptide deformylase inhibitor, comprising the following steps:

[0026] S1: Compound 2 (an acyl hydrazine compound) is prepared by reacting the carboxyl group of compound 1 with hydrazine hydrate under the action of condensing agent CDI.

[0027] S2: Under the action of condensing agents EDCI, HOBT, and NMM, compound 2 reacts with the carboxyl group in compound A (Boc-protected L-proline) to form compound 3;

[0028] S3: Compound 3 undergoes cyclization under the action of Lawson's reagent to form compound 4 (a 1,3,4-thiadiazole compound);

[0029] S4: Compound 4 reacts in trifluoroacetic acid and dichloromethane to give compound 5;

[0030] S5: Compound 5 and compound B condensed under the action of HATU and DIPEA to give compound 6;

[0031] S6: Compound 6 is reacted in trifluoroacetic acid and dichloromethane to give compound 7, which is the 1,3,4-thiadiazole peptide deformylase inhibitor.

[0032] The structures of compounds 1, 2, A, 3, 4, 5, B, 6, and 7, as well as the preparation process of the 1,3,4-thiadiazole peptide deformylase inhibitor, are shown below:

[0033]

[0034] In one embodiment of the present invention, in step S1, the molar ratio of compound 1 to CDI and hydrazine hydrate is 1.0:1.1-2.0:2.0-5.0, the reaction temperature of step S1 is 0-40°C, and the reaction time is 5-24 hours.

[0035] In one embodiment of the present invention, in step S2, the molar ratio of compound 2 to compound A, EDCI, HOBT, and NMM is 1.0:1.1-1.5:1.0-2.0:1.0-2.0:2.0-5.0, the reaction temperature of step S2 is 0-40°C, and the reaction time is 5-24 hours.

[0036] In one embodiment of the present invention, in step S3, the molar ratio of compound 3 to Lawson's reagent is 1.0:1.0-1.5, the reaction temperature in step S3 is 80-120°C, and the reaction time is 1-12 hours.

[0037] In one embodiment of the present invention, in step S4, the molar ratio of compound 4 to trifluoroacetic acid is 1.0:5.0-25, the reaction temperature of step S4 is 0-40°C, and the reaction time is 1-10 hours.

[0038] In one embodiment of the present invention, in step S5, the molar ratio of compound 5 to compound B, HATU, and DIPEA is 1.0:1.1-1.5:1.2-3.0:2.0-5.0, the reaction temperature in step S5 is 0-40°C, and the reaction time is 5-24 hours.

[0039] In one embodiment of the present invention, in step S6, the molar ratio of compound 6 to trifluoroacetic acid is 1.0:5.0-25, the reaction temperature of step S6 is 0-40°C, and the reaction time is 1-10 hours.

[0040] The present invention further provides pharmaceutically acceptable salts of the aforementioned 1,3,4-thiadiazole peptide deformylase inhibitors. A pharmaceutically acceptable salt is defined as a salt of a compound that, within a reliable pharmaceutical evaluation range, is suitable for contact with tissues of humans or lower animals without undue toxicity, irritation, or allergic reactions, has a reasonably reasonable benefit-risk ratio, is typically water- or oil-soluble or dispersible, and is effectively used for its intended purpose. Pharmaceutically acceptable salts can be obtained using conventional techniques skilled in the art.

[0041] The present invention further provides a solvate of the aforementioned 1,3,4-thiadiazole peptide deformylase inhibitor. The solvate can be obtained using conventional techniques skilled in the art.

[0042] The present invention further provides the use of the 1,3,4-thiadiazole peptide deformylase inhibitor, its pharmaceutically acceptable salt, or its solvates in the preparation of a medicament for inhibiting bacteria.

[0043] In one embodiment of the invention, the use of the 1,3,4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for inhibiting drug-resistant bacteria is provided.

[0044] Furthermore, the use of the 1,3,4-thiadiazole peptide deformylase inhibitor, its pharmaceutically acceptable salt, or a solvate thereof in the preparation of a medicament for inhibiting Gram-positive or Gram-negative drug-resistant bacteria is provided.

[0045] Furthermore, the use of the 1,3,4-thiadiazole peptide deformylase inhibitor, its pharmaceutically acceptable salt, or a solvate thereof in the preparation of a medicament for inhibiting drug-resistant Acinetobacter baumannii is provided.

[0046] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0047] 1. The 1,3,4-thiadiazole peptide deformylase inhibitors provided by this invention can effectively inhibit bacterial protein synthesis, thereby achieving sterilization. These compounds exhibit excellent inhibitory activity against Gram-positive drug-resistant bacteria, especially the clinically challenging methicillin-resistant Staphylococcus aureus (MRSA). In particular, some optimized compounds show inhibitory activity 4-8 times that of the control compounds vancomycin and linezolid.

[0048] 2. The 1,3,4-thiadiazole peptide deformylase inhibitors provided by this invention also exhibit inhibitory activity against Gram-negative drug-resistant bacteria, especially against drug-resistant Acinetobacter baumannii, which is known as a "superbug," with an inhibitory activity of 0.5 μg / mL, which is far superior to marketed drugs such as vancomycin and linezolid. Detailed Implementation

[0049] The present invention will now be described in detail with reference to specific embodiments.

[0050] When the 1,3,4-thiadiazole peptide deformylase inhibitor is selected from the following structures...

[0051]

[0052] R 2 Using 4-nitrobenzoic acid as an example, this paper specifically demonstrates a general synthetic method for deformylase inhibitors of this class of 1,3,4-thiadiazole peptides. Using this general synthetic method, by changing R... 1 R 2 The group can be used to synthesize all other compounds.

[0053] Example 1.4 Synthesis of 4-nitrobenzoylhydrazine

[0054]

[0055] Weigh 5.0 g of 4-nitrobenzoic acid and dissolve it in 37.5 mL of tetrahydrofuran. Add 6.3 g of N,N'-carbonyldiimidazole (CDI) and stir at room temperature for 4 h. After the 4-nitrobenzoic acid has reacted completely, add the reaction solution dropwise to 5.8 g of 80% hydrazine monohydrate in 25 mL of THF and stir at room temperature for 12 h. After the reaction is complete, distill off the THF. Add 30 mL of ethyl acetate and 30 mL of water to the residue and stir for 15 min. Separate the solutions. Extract the aqueous phase three times with ethyl acetate. Combine the organic phases and dry the organic layer with anhydrous sodium sulfate, then evaporate to dryness to obtain a yellow solid product. The product can be used directly in the next reaction.

[0056] Example 2. (S)-2-(2-(4-nitrobenzoyl)hydrazide-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0057]

[0058] (S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.8 g), 1-hydroxybenzotriazole (4.4 g), and dichloromethane (90 mL) were added to a reaction flask and cooled to 0 °C. Then, N-methylmorpholine (13.5 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.6 g), and the product obtained in the previous step were added to the reaction flask. The mixture was brought to room temperature and stirred for 12 h. After the reaction was complete, the reaction solution was washed twice with water, twice with 1 mol / L hydrochloric acid solution, and twice with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain 6.9 g of a pale yellow solid, with a yield of 61%.

[0059] 1 H NMR (400MHz, CDCl3) δ9.75(s,1H),9.41(s,1H),8.26(d,J=8.7Hz,2H),8.00(d,J=8.7Hz,2H ),4.42(s,1H),3.57–3.25(m,2H),2.30(d,J=43.0Hz,1H),2.14–1.87(m,3H),1.49(s,9H).

[0060] Example 3. (S)-2-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0061]

[0062] Step 3: Dissolve the above reaction product (3.8 g) in 1,4-dioxane (65 mL), add Lawson's reagent (4.4 g), heat to 115 °C, reflux for 3 h, cool to room temperature, quench the reaction with water, and extract three times with ethyl acetate. Wash the organic phase twice with saturated sodium chloride solution and twice with saturated sodium bicarbonate solution. Dry the washed organic phase with anhydrous sodium sulfate and concentrate it. Finally, purify the product by EA:PE 1:3 (v / v) column chromatography to obtain 1.5 g of product, yield 40%.

[0063] 1 H NMR (400MHz, CDCl3) δ8.27(d,J=7.1Hz,2H),8.06(d,J=8.8Hz,2H),5.26(s,1H ),3.67–3.28(m,2H),2.67–2.15(m,2H),1.97(s,2H),1.37(d,J=46.9Hz,9H).

[0064] Example 4. (S)-2-(4-nitrophenyl)-5-(pyrrolidone-2-yl)-1,3,4-thiadiazole

[0065]

[0066] The reaction product (0.88 g) obtained in step 3 was dissolved in dichloromethane (6 mL), followed by trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 4 hours until the reaction was complete. After evaporation, the product was dissolved in 6 mL of dichloromethane and washed three times with saturated sodium bicarbonate solution. The dichloromethane layer was dried and then evaporated to dryness to obtain 0.6200 g of a yellow solid product, with a yield of 95%. The product did not require purification and was directly used in the next reaction step.

[0067] Example 5. N-((4-methoxybenzyl)oxy)-N-((R)-2-((S)-2-(5-(4-nitrophenyl)1,3,4-thiadiazol-2-yl)pyrrolidine-1-formyl)hexyl)formamide

[0068]

[0069] Weigh (R)-2-((N-((4-methoxybenzyl)oxy)formamido)methyl)hexanoic acid (0.09 g, 0.3 mmol, synthesized according to the method reported in European Journal of Medicinal Chemistry, 86(2014)133e152), dissolve in dichloromethane (2 mL), then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (0.13 g) and DIPEA (0.11 g), and stir at room temperature for 20 min. Then add the above reaction solution and stir at room temperature for 10 h. After the reaction is complete, the reaction solution is washed twice with 1 mol / L hydrochloric acid solution and twice with saturated sodium bicarbonate solution. The washed organic phase is dried over anhydrous sodium sulfate and concentrated to obtain crude product, which is then purified by column chromatography to obtain 0.0943 g of product, with a yield of 55%.

[0070] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=8.8Hz,2H),8.10(d,J=8.7Hz,2H),7.85(dd,J=21.6,12 .7Hz,1H),7.46–7.28(m,2H),6.96–6.79(m,2H),5.36(d,J=6.4Hz,1H),5.01–4.57(m,2 H),3.81(d,J=5.0Hz,3H),3.80–3.70(m,2H),3.61(t,J=13.3Hz,2H),2.64(d,J=14.1Hz ,1H),2.20(d,J=7.9Hz,2H),1.99(d,J=37.4Hz,2H),1.25(s,6H),0.82(t,J=7.0Hz,3H).

[0071] Example 6. N-hydroxy-N-((R)-2-((S)-2-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)pyrrolidine-1-acyl)hexyl)formamide

[0072]

[0073] The above product (0.0943 g, 0.17 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (1 mL). The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the dichloromethane was distilled off. The residue was dissolved in dichloromethane (4 mL), and the organic phase was washed with saturated sodium bicarbonate solution (4 mL) until alkaline. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain the crude product. Finally, the product was purified by column chromatography to obtain 50 mg of the product, with a yield of 66%.

[0074] 1H NMR (400MHz, CDCl3) δ8.34 (d, J=8.8Hz, 2H), 8.09 (d, J=8.9Hz, 2H), 5.54 (dd, J= 7.3,2.5Hz,1H),3.94–3.79(m,2H),3.76–3.60(m,2H),3.18(dd,J=6.8,3.5Hz,1 H),2.63–2.40(m,1H),2.28(dd,J=12.3,7.5Hz,2H),2.15(s,1H),1.70–1.52(m, 2H),1.31(dd,J=5.7,3.4Hz,4H),0.86(d,J=3.2Hz,3H).HRMS(ESI):calculated for C 20 H 25 N5O5S[M+Na] + =470.1474, found 470.1496.

[0075] Other representative compounds:

[0076] Compound 20:

[0077]

[0078] 1 H NMR (400MHz, CDCl3) δ8.61 (dd, J=8.6, 7.1Hz, 1H), 8.19 (dd, J=8.7, 1.8Hz, 1H), 8.15– 8.08(m,1H),7.86(s,1H),5.65(dd,J=21.7,7.4Hz,1H),3.95(d,J=18.6Hz,1H),3.77( dd,J=22.5,10.8Hz,3H),3.23(s,1H),2.64(s,1H),2.44–2.25(m,2H),2.17(s,1H),1. 63(d,J=7.6Hz,2H),1.36–1.27(m,4H),0.86(t,J=5.8Hz,3H).HRMS(ESI):calculated for C 20 H 24 FN5O5S[M+Na] + =488.1374, found 488.1360

[0079] Compound 29:

[0080]

[0081] 1H NMR(400MHz, CDCl3)δ7.79(s,1H),7.54–7.38(m,2H),7.18–7.02(m,1H),5.65–5.37(m,1H),3.84(dt,J=16.5,10.6Hz,2H),3.73–3.59(m,2H) ,3.46(s,1H),2.64(d,J=48.9Hz,1H),2.26(dd,J=22.6,16.3Hz,2H),2.11(s,1H),1.64(d,J=27.3Hz,2H),1.29(s,4H),0.87(t,J=6.2Hz,3H).

[0082] HRMS(ESI): calculated for C 18 H 24 N4O3S2[M+Na] + =431.1182,found 431.1183

[0083] Compound 33:

[0084]

[0085] 1 H NMR(400MHz, CDCl3)δ7.89(d,J=4.2Hz,1H),7.78(s,1H),7.38(d,J=4.2Hz,1H), 5.55(d,J=5.5Hz,1H),3.98–3.79(m,2H),3.69(dd,J=16.8,10.2Hz,1H),3.54–3 .38(m,1H),3.19(d,J=6.4Hz,1H),2.70(d,J=3.2Hz,1H),2.43–2.24(m,2H),2.1 6(s,1H),1.59(d,J=6.2Hz,1H),1.46(s,1H),1.29(s,4H),0.85(t,J=6.4Hz,3H).

[0086] HRMS(ESI): calculated for C 18 H 23 N5O5 S2[M+Na] + =476.1038, found 476.1031

[0087] When the 1,3,4-thiadiazole peptide deformylase inhibitor provided by this invention is selected from the structure of the following formula (2),

[0088]

[0089] Its R 2 The minimum inhibitory concentrations (MIC, μg / mL) against MRSA1, MSSA1, S. epidermidis, E. coli, and A. baumannii under different selections are shown in Table 1.

[0090] Antibacterial activity was determined using the microdilution method. First, a series of sample solutions with concentrations of 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.3, 0.16, and 0.08 μg / mL were prepared. Then, 1 mL of each sample solution was added to a 9cm sterile agar plate, followed by 9 mL of blood agar medium. The plates were immediately mixed and allowed to solidify on a water platform to obtain drug-containing plates with concentrations of 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.016, and 0.008 μg / mL. Finally, the bacterial suspension was added to the corresponding wells of a 96-well plate in numerical order and placed in a multi-point inoculation instrument. Each prepared drug-containing plate was inoculated in ascending order of concentration. The plates were inverted and incubated at 35℃ for 16 hours. The results were observed and the growth status was recorded.

[0091] Compound R shown in Table 1 (2) 2 Minimum inhibitory concentration (MIC, μg / mL) for different selections

[0092]

[0093]

[0094]

[0095]

[0096]

[0097] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A 1,3,4-thiadiazole peptide deformylase inhibitor, characterized in that, The structural formula is shown in equation (1): Equation (1) Among them, R 1 It is n-butyl; R 2 It can be hydrogen, straight-chain alkanes, cyclic alkanes, aromatic rings, or heterocycles; R 2 The cyclic alkane group is selected from one of the following structures: , , or ; R 2 The straight-chain alkanes of the group are selected from ; R 2 The aromatic ring of the group is selected from one of the following structures: ； R 2 The heterocycle of the group is selected from one of the following structures: 。 2. The 1,3,4-thiadiazole peptide deformylase inhibitor according to claim 1, characterized in that, 1,3,4-Thiadiazole peptide deformylase inhibitors are selected from one of the following structures: 、 、 ； Bu is n-butyl.

3. The method for preparing the 1,3,4-thiadiazole peptide deformylase inhibitor according to claim 1 or 2, characterized in that, Includes the following steps: S1: Compound 2 was prepared by reacting the carboxyl group in compound 1 with hydrazine hydrate in the solvent THF under the action of condensing agent CDI; S2: Under the action of condensing agents EDCI, HOBt, and NMM, compound 2 reacts with the carboxyl group in compound A in dichloromethane to form compound 3; S3: Compound 3 undergoes cyclization under the action of Lawson's reagent to form compound 4; S4: Compound 4 reacts in trifluoroacetic acid and dichloromethane to give compound 5; S5: Compound 5 and compound B condensed in dichloromethane under the action of HATU and DIPEA to give compound 6; S6: Compound 6 is reacted in trifluoroacetic acid and dichloromethane to give compound 7, which is the 1,3,4-thiadiazole peptide deformylase inhibitor. The preparation route for 1,3,4-thiadiazole peptide deformylase inhibitors is shown below: 。 4. The method for preparing the 1,3,4-thiadiazole peptide deformylase inhibitor according to claim 3, characterized in that, In step S1, the molar ratio of compound 1 to CDI and hydrazine hydrate is 1.0:1.1 to 2.0:2.0 to 5.0, the reaction temperature in step S1 is 0-40 °C, and the reaction time is 5-24 hours. In step S2, the molar ratio of compound 2 to compound A, EDCI, HOBT, and NMM is 1.0:1.1-1.5:1.0-2.0:1.0-2.0:2.0-5.0, the reaction temperature in step S2 is 0-40 °C, and the reaction time is 5-24 hours. In step S3, the molar ratio of compound 3 to Lawson's reagent is 1.0:1.0-1.5, the reaction temperature in step S3 is 80-120 °C, and the reaction time is 1-12 hours. In step S4, the molar ratio of compound 4 to trifluoroacetic acid is 1.0:5.0-25, the reaction temperature of step S4 is 0-40℃, and the reaction time is 1-10 hours. In step S5, the molar ratio of compound 5 to compound B, HATU, and DIPEA is 1.0:1.1-1.5:1.2-3.0:2.0-5.0, the reaction temperature in step S5 is 0-40 °C, and the reaction time is 5-24 hours. In step S6, the molar ratio of compound 6 to trifluoroacetic acid is 1.0:5.0-25, the reaction temperature of step S6 is 0-40℃, and the reaction time is 1-10 hours.

5. A pharmaceutically acceptable salt of the 1,3,4-thiadiazole peptide deformylase inhibitor of claim 1 or 2.

6. The use of the 1,3,4-thiadiazole peptide deformylase inhibitor of claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting bacteria.

7. The application according to claim 6, characterized in that, The use of the 1,3,4-thiadiazole peptide deformylase inhibitors and their pharmaceutically acceptable salts in the preparation of drugs for inhibiting drug-resistant bacteria.

8. The application according to claim 7, characterized in that, The use of the 1,3,4-thiadiazole peptide deformylase inhibitors and their pharmaceutically acceptable salts in the preparation of medicaments for inhibiting Gram-positive or Gram-negative drug-resistant bacteria.

9. The application according to claim 7, characterized in that, The use of the 1,3,4-thiadiazole peptide deformylase inhibitor and its pharmaceutically acceptable salt in the preparation of a medicament for inhibiting drug-resistant Acinetobacter baumannii.

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