CN117886808A - 1,3, 4-thiadiazole peptide deformylase enzyme inhibitor and preparation and application thereof - Google Patents

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

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CN117886808A
CN117886808A CN202311693815.8A CN202311693815A CN117886808A CN 117886808 A CN117886808 A CN 117886808A CN 202311693815 A CN202311693815 A CN 202311693815A CN 117886808 A CN117886808 A CN 117886808A
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thiadiazole
peptide deformylase
deformylase inhibitor
inhibitor
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杨嬅嬿
杨守宁
王亚如
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University of Shanghai for Science and Technology
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Abstract

The invention relates to a1, 3, 4-thiadiazole peptide deformylase enzyme inhibitor and preparation and application thereof. The structural formula is shown as formula (1):wherein R is 1 N-butyl or cyclopentylmethyl; r is R 2 Is hydrogen, straight-chain alkane, cyclic alkane, aromatic ring, substituted biphenyl or heterocycle. The 1,3, 4-thiadiazole peptide deformylase inhibitor provided by the invention can effectively inhibit bacterial synthesis of protein, thereby achieving the aim of sterilization. The compounds are particularly clinically troublesome to gram-positive resistant bacteria, particularly methicillin-resistant Lin Putao cocci (MRSA) exhibits excellent inhibitory activity, especially for a fraction of the preferred compounds, up to 4-8 times the inhibitory activity of the control vancomycin, linezolid. The 1,3, 4-thiadiazole peptide deformylase inhibitor provided by the invention also shows the inhibition activity on gram-negative drug-resistant bacteria, especially drug-resistant Acinetobacter baumannii called super bacteria, and the inhibition activity reaches 0.5 mug/mL, which is far superior to vancomycin and linezolid.

Description

1,3, 4-thiadiazole peptide deformylase enzyme inhibitor and preparation and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a1, 3, 4-thiadiazole peptide deformylase inhibitor and preparation and application thereof.
Background
Diseases caused by microbial infection, such as plague, tuberculosis, cholera, etc., have historically caused tremendous population attenuation. Until the appearance of antibiotics, humans are really taking initiative when facing bacteria. Penicillin is the earliest antibiotic found and used to clinically treat patients with bacterial infections, and over time, more and more antibiotics are found and used to treat patients with bacterial infectious diseases.
However, humans use antibiotics to combat bacteria, and bacteria also develop resistance through evolution. Studies have shown that bacteria are largely defensive to antibiotics using two genetic strategies: 1. genetic mutations, usually associated with the mechanism of action of antibacterial compounds, as bacteria accumulate during evolution with each genetic mutation, bacteria acquire various drug-resistant genes, also known as "natural drug resistance"; 2. exogenous DNA encoding a drug resistance determinant is obtained by horizontal gene transfer and is referred to as "acquired drug resistance". Acquired resistance enables transfer of drug-resistant genes between strains, resulting in multiple resistance, such as NDM-1 super-resistant enterobacteriaceae, which occur in india. Thus, bacterial drug-resistant (Antimicrobial Resistance, AMR) infections have become increasingly a new challenge in new centuries of anti-infective therapy, a major threat to human health and life in the world today.
Existing antibiotics mostly exert inhibitory effects against three important aspects of the bacterial growth cycle: bacterial cell wall synthesis, ribosomal protein synthesis, and DNA replication. It is becoming increasingly difficult to design new antibiotics that are able to combat resistant bacteria by attacking the same set of targets. Therefore, in the face of bacterial resistance, we have urgent need to find new antibacterial targets and develop antibacterial drugs with multiple drug resistance mechanisms.
The peptide deformylase (Peptide Deformylase, PDF) is a ferrous ion-containing (Fe) 2+ ) Is widely present in bacteria. During protein synthesis in prokaryotes, the start codon encodes for formylmethionine and, under catalysis by the formylase, methionine-tRNAf (Met-RNAfMet) to formylmethionine-tRNAf (Formyl-Met-RNAfMet) to participate in the initial phase of the synthesis of the prokaryotic peptide chain, whereas tRNAm carries the normal methionine to participate in the synthesis of the peptide chain, and the nascent polypeptide is obtained by extension, termination and release of the peptide chain. The nascent polypeptides are not all biologically active and must be processed and modified to become mature proteins. The nascent polypeptide is subjected to N-terminal formyl removal under the catalysis of peptide deformylase, and methionine residues are removed by methionine aminopeptidase (Methionine Aminopeptidase, MAP) to finally synthesize the active protein. Therefore, by inhibiting peptide deformylase, protein synthesis is arrested in the N-terminal formyl removal stage, and bacterial growth can be effectively inhibited. At present, peptide deformylase is taken as an antibacterial target, more researches are carried out, four medicines (peptide deformylase inhibitors) are moved to a clinical stage, namely compounds BB83698, LBM415, GSK1322322 and IDP-73152, and the structures are respectively as follows:
however, there is a common problem with currently under investigation PDF inhibitors: the peptide PDF inhibitor can generate stronger oxidative metabolites in the metabolic process of human bodies, and causes methemoglobin of organisms. Another disadvantage of PDF inhibitors is the narrow antimicrobial spectrum, although PDF is widely present in bacteria, due to differences in bacterial structure, most PDF inhibitors currently under investigation are effective only against gram-positive bacteria, with little inhibition against gram-negative bacteria.
Disclosure of Invention
Based on the problems that the existing peptidomimetic PDF inhibitor can generate stronger oxidative metabolites in the human metabolism process to cause hyperhemoglobinaemia of organisms, and the PDF inhibitor is mainly effective only on gram-positive bacteria and has almost no inhibition effect on gram-negative bacteria, the invention provides a1, 3, 4-thiadiazole peptide deformylase inhibitor and preparation and application thereof.
The invention researches and analyzes the common problem existing in the research of PDF inhibitors (the peptide-like PDF inhibitors can generate stronger oxidative metabolites in the metabolic process of human bodies to cause hyperhemoglobin hematoma of organisms), wherein the reason is probably that after the medicaments containing amide bonds enter the human bodies, the medicaments are firstly hydrolyzed into phenylamine derivatives, N-phenylhydroxylamine is generated after enzyme metabolism in the liver, and a small amount of N-phenylhydroxylamine can oxidize a large amount of hemoglobin into the hyperhemoglobin to reduce the number of the hemoglobin in the blood to cause the reduction of blood oxygen concentration and cause the organisms to have hypoxia symptoms.
In order to avoid the adverse reaction of methemoglobin, the PDF inhibitor structure should be optimized, the amide bond in the compound is reduced, and the generation of N-phenyl hydroxylamine is avoided or greatly reduced.
The 1,3, 4-thiadiazole peptide deformylase inhibitor provided by the invention is a novel peptide deformylase inhibitor antibacterial drug containing 1,3, 4-thiadiazole, and can effectively kill bacteria with drug resistance to the existing antibiotics. Unlike available PDF inhibitor capable of killing gram-positive bacteria, the compound of the present invention has excellent gram-positive bacteria and gram-negative bacteria killing capacity. In addition, the 1,3, 4-thiadiazole is used for replacing an amide bond in the original peptidomimetic PDF inhibitor, so that the use of aniline building blocks can be avoided, the generation of N-phenyl hydroxylamine in metabolites is effectively reduced or avoided, and the formation of methemoglobin is reduced.
The aim of the invention can be achieved by the following technical scheme:
the invention firstly provides a1, 3, 4-thiadiazole peptide deformylase inhibitor, the structural formula of which is shown as the formula (1):
wherein R is 1 N-butyl or cyclopentylmethyl; r is R 2 Is hydrogen, straight-chain alkane, cyclic alkane, aromatic ring, substituted biphenyl or heterocycle.
In one of the present inventionIn embodiments, R 2 The cyclic alkane of the group is selected from one of the following structures:
in one embodiment of the invention, R 2 The linear alkane of the radical is selected from
In one embodiment of the invention, R 2 The aromatic ring of the group is selected from one of the following structures:
in one embodiment of the invention, R 2 The heterocyclic ring of the group is selected from one of the following structures:
in one embodiment of the invention, the 1,3, 4-thiadiazole peptide deformylase inhibitor is selected from one of the following structures:
the invention further provides a preparation method of the 1,3, 4-thiadiazole peptide deformylase inhibitor, which comprises the following steps:
s1: the carboxyl in the compound 1 reacts with hydrazine hydrate under the action of condensing agent CDI to prepare a compound 2 (a hydrazide compound);
s2: reacting compound 2 with the carboxyl group in compound a (Boc-protected L-proline) under the action of condensing agent EDCI, HOBT, NMM to form compound 3;
s3: compound 3 forms compound 4 (which is a1, 3, 4-thiadiazole compound) by ring closure under the action of a lawson reagent;
s4: reacting the compound 4 in trifluoroacetic acid and dichloromethane to obtain a compound 5;
s5: condensing the compound 5 with the compound B under the action of HATU and DIPEA to obtain a compound 6;
s6: reacting the compound 6 in trifluoroacetic acid and dichloromethane to obtain a compound 7, namely the 1,3, 4-thiadiazole peptide deformylase inhibitor;
the structures of the compound 1, the compound 2, the compound A, the compound 3, the compound 4, the compound 5, the compound B, the compound 6 and the compound 7 and the preparation process of the 1,3, 4-thiadiazole peptide deformylase inhibitor are shown as follows:
in one embodiment of the present invention, in step S1, the molar ratio of the compound 1 to CDI and hydrazine hydrate is 1.0:1.1 to 2.0:2.0 to 5.0, and the reaction temperature in step S1 is 0 to 40℃and the reaction time is 5 to 24 hours.
In one embodiment of the present invention, in step S2, the molar ratio of the compound 2 to the compound A, EDCI, HOBT, NMM is 1.0:1.1 to 1.5:1.0 to 2.0:1.0 to 2.0:2.0 to 5.0, and the reaction temperature in step S2 is 0 to 40 ℃ and the reaction time is 5 to 24 hours.
In one embodiment of the present invention, in step S3, the molar ratio of the compound 3 to the Lawsen agent is 1.0:1.0 to 1.5, the reaction temperature in step S3 is 80 to 120℃and the reaction time is 1 to 12 hours.
In one embodiment of the present invention, in step S4, the molar ratio of the compound 4 to trifluoroacetic acid is 1.0:5.0 to 25, the reaction temperature in step S4 is 0 to 40 ℃, and the reaction time is 1 to 10 hours.
In one embodiment of the present invention, in step S5, the molar ratio of the compound 5 to the compound B, HATU, DIPEA is 1.0:1.1 to 1.5:1.2 to 3.0:2.0 to 5.0, and the reaction temperature in step S5 is 0 to 40 ℃ and the reaction time is 5 to 24 hours.
In one embodiment of the present invention, in step S6, the molar ratio of the compound 6 to trifluoroacetic acid is 1.0:5.0-25, the reaction temperature in step S6 is 0-40℃and the reaction time is 1-10 hours.
The invention further provides pharmaceutically acceptable salts of the 1,3, 4-thiadiazole peptide deformylase inhibitor. Pharmaceutically acceptable salts means that, within the scope of reliable pharmaceutical evaluation, the salts of the compounds are suitable for contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit to risk ratio, generally water or oil soluble or dispersible, and effective for their intended use. Pharmaceutically acceptable salts thereof can be obtained according to conventional technical means by those skilled in the art.
The invention further provides solvates of the 1,3, 4-thiadiazole peptide deformylase inhibitor. The solvates thereof may be obtained according to conventional technical means for those skilled in the art.
The invention further provides application of the 1,3, 4-thiadiazole peptide deformylase inhibitor, pharmaceutically acceptable salt or solvate thereof in preparing medicines for inhibiting bacteria.
In one embodiment of the invention, there is provided the use of the 1,3, 4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a medicament for inhibiting drug-resistant bacteria.
Further, the application of the 1,3, 4-thiadiazole peptide deformylase inhibitor, the pharmaceutically acceptable salt or the solvate thereof in preparing medicines for inhibiting gram-positive drug-resistant bacteria or gram-negative drug-resistant bacteria is provided.
Still further, there is provided an application of the 1,3, 4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof in preparing a medicament for inhibiting drug-resistant acinetobacter baumannii.
Compared with the prior art, the invention has the following advantages:
1. the 1,3, 4-thiadiazole peptide deformylase inhibitor provided by the invention can effectively inhibit bacterial synthesis of protein, thereby achieving the aim of sterilization. The compound shows excellent inhibitory activity on gram-positive drug-resistant bacteria, particularly on clinically troublesome methicillin-resistant Lin Putao cocci (MRSA), particularly on optimized partial compounds, and the inhibitory activity of the compound reaches 4-8 times of that of reference substances vancomycin and linezolid.
2. The 1,3, 4-thiadiazole peptide deformylase inhibitor provided by the invention also shows the inhibition activity on gram-negative drug-resistant bacteria, especially drug-resistant Acinetobacter baumannii called super bacteria, and the inhibition activity reaches 0.5 mug/mL, which is far superior to the marketed drugs such as vancomycin, linezolid and the like.
Detailed Description
The present invention will be described in detail with reference to specific examples.
When the 1,3, 4-thiadiazole peptide deformylase inhibitor is selected from the following structures,
R 2 the general synthesis of such 1,3, 4-thiadiazole peptide deformylase inhibitors is shown in detail by the column of =4-nitrobenzoic acid. By using the general synthesis method, R is replaced 1 、R 2 The group can be synthesized to obtain all other compounds.
EXAMPLE 1 Synthesis of 4-nitrobenzoyl hydrazine
4-Nitrophenyl benzoic acid (5.0 g) was weighed and dissolved in tetrahydrofuran (37.5 mL), N' -Carbonyldiimidazole (CDI) (6.3 g) was added and stirred at room temperature for 4h, after the 4-nitrobenzoic acid reaction was completed, the reaction was added dropwise to 80% hydrazine monohydrate (5.8 g) of THF (25 mL) and stirred at room temperature for 12h. After completion of the reaction, THF was distilled off, ethyl acetate (30 mL), water (30 mL) was added to the residue, stirred for 15min, the liquid was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and the organic layer was dried over anhydrous sodium sulfate and dried by spin-drying to give a yellow solid product. The product was used directly in the next reaction.
EXAMPLE 2 (S) -2- (2- (4-nitrobenzoyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester
To the reaction flask was added (S) -1- (t-butoxycarbonyl) pyrrolidine-2-carboxylic acid (5.8 g), 1-hydroxybenzotriazole (4.4 g), methylene chloride (90 mL) and cooled to 0deg.C. N-methylmorpholine (13.5 mL), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.6 g) and the product from the above step were then added to the reaction flask, warmed to room temperature and stirred for 12h. After the reaction was completed, the reaction solution was washed with water 2 times, 1mol/L hydrochloric acid solution was washed twice, saturated sodium bicarbonate solution was washed 2 times, and the organic layer was dried over anhydrous sodium sulfate and then was dried by spin-drying, followed by purification by silica gel column chromatography to give 6.9g of a pale yellow solid product in 61% yield.
1 H NMR(400MHz,CDCl 3 )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).
EXAMPLE 3 (S) -2- (5- (4-nitrophenyl) -1,3, 4-thiadiazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Step 3: the reaction product (3.8 g) was dissolved in 1, 4-dioxane (65 mL), L-Lawson's reagent (4.4 g) was added, heated to 115℃and reacted for 3h at reflux, cooled to room temperature, quenched with water, extracted 3 more times with ethyl acetate, and the organic phase was washed 2 times with saturated sodium chloride solution and twice with saturated sodium bicarbonate solution. The washed organic phase was dried over anhydrous sodium sulfate and concentrated, and finally purified by EA:PE 1:3 (v/v) column chromatography to give 1.5g of product in 40% yield.
1 H NMR(400MHz,CDCl 3 )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).
EXAMPLE 4 (S) -2- (4-nitrophenyl) -5- (pyrrolidin-2-yl) -1,3, 4-thiadiazole
Dichloromethane (6 mL) was added to the reaction product (0.88 g) obtained in step 3 to dissolve, trifluoroacetic acid (6 mL) was added thereto, stirring was carried out at room temperature for 4 hours, after the reaction was completed, 6mL of dichloromethane was added to dissolve, washing was carried out 3 times with saturated sodium bicarbonate solution, and after the dichloromethane layer was dried, the yellow solid product was obtained as 0.6200g, the yield was 95%. The product was directly subjected to the next reaction without purification.
Example 5N- ((4-methoxybenzyl) oxy) -N- ((R) -2- ((S) -2- (5- (4-nitrophenyl) 1,3, 4-thiadiazol-2-yl) pyrrolidin-1-formyl) hexyl) carboxamide
(R) -2- ((N- ((4-methoxybenzyl) oxy) carboxamido) methyl) hexanoic acid (0.09 g,0.3mmol, synthesized by the preparation method reported in reference European Journal of Medicinal Chemistry,86 (2014) 133e 152) was weighed, dichloromethane (2 mL) was added for dissolution, and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (0.13 g), DIPEA (0.11 g) was added and stirred at room temperature for 20min. Then, the reaction mixture was added and stirred at room temperature for 10 hours. After the reaction was completed, the reaction solution was washed twice with 1mol/L hydrochloric acid solution and 2 times with saturated sodium bicarbonate solution, and the washed organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography to obtain 0.0943g of the product with a yield of 55%.
1 H NMR(400MHz,CDCl 3 )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,2H),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).
EXAMPLE 6N-hydroxy-N- ((R) -2- ((S) -2- (5- (4-nitrophenyl) -1,3, 4-thiadiazol-2-yl) pyrrolidin-1-yl) hexyl) carboxamide
The above-mentioned product (0.0943 g,0.17 mmol) was dissolved by adding methylene chloride (2 mL), trifluoroacetic acid (1 mL) was further added, stirring was carried out at 0℃for 3 hours, after the reaction was completed, methylene chloride was distilled off, the residue was dissolved by adding methylene chloride (4 mL), the organic phase was washed with saturated sodium bicarbonate solution (4 mL) until it became alkaline, the organic phase was dried over anhydrous sodium sulfate sodium and then dried by spinning to obtain a crude product, and finally, 50mg of the product was obtained by column chromatography purification in 66% yield.
1 H NMR(400MHz,CDCl 3 )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,1H),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 N 5 O 5 S[M+Na] + ＝470.1474,found 470.1496.
Some other representative compounds:
compound 20:
1 H NMR(400MHz,CDCl 3 )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 FN 5 O 5 S[M+Na] + ＝488.1374,found 488.1360
compound 29:
1 H NMR(400MHz,CDCl 3 )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).
HRMS(ESI):calculated for C 18 H 24 N 4 O 3 S 2 [M+Na] + ＝431.1182,found 431.1183
compound 33:
1 H NMR(400MHz,CDCl 3 )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),2.16(s,1H),1.59(d,J＝6.2Hz,1H),1.46(s,1H),1.29(s,4H),0.85(t,J＝6.4Hz,3H).
HRMS(ESI):calculated for C 18 H 23 N 5 O 5 S 2 [M+Na] + ＝476.1038,found 476.1031
when the 1,3, 4-thiadiazole peptide deformylase inhibitor provided by the invention is selected from the following structures of formula (2),
r of which is R 2 The minimum inhibitory concentrations (MIC, μg/mL) of MRSA1, MSSA1, S.epider midi, E.coli, A.baumannii are shown in Table 1 at various selections.
The antibacterial activity is measured by adopting a micro dilution method, namely, serial sample solutions with the concentrations of 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.3, 0.16 and 0.08 mug/mL are firstly prepared, then 1mL of the sample solution is respectively taken and added into a 9cm sterile plate, 9mL of blood agar culture medium is added, the mixture is immediately mixed uniformly, and a horizontal platform is placed for coagulation to obtain a medicine-containing plate with the concentrations of 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.016 and 0.008 mug/mL in sequence. And finally, adding the test bacterial suspension into corresponding holes of the 96-well plate according to the serial number sequence, and placing the test bacterial suspension in a multipoint inoculator. Inoculating each prepared medicated plate according to the order of low concentration to high concentration. The cells were incubated at 35℃for 16 hours in an inverted state, and the observed results were taken out and recorded for growth.
TABLE 1 Compounds R of formula (2) 2 Minimum inhibitory concentration (MIC, μg/mL) at various selections
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The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.

Claims (10)

1. The 1,3, 4-thiadiazole peptide deformylase inhibitor is characterized by having a structural formula shown in a formula (1):
wherein R is 1 N-butyl or cyclopentylmethyl; r is R 2 Is hydrogen, straight-chain alkane, cyclic alkane, aromatic ring, substituted biphenyl or heterocycle.
2. A1, 3, 4-thiadiazole peptide deformylase inhibitor according to claim 1, wherein R 2 The cyclic alkane of the group is selected from one of the following structures:
R 2 the linear alkane of the radical is selected from
R 2 The aromatic ring of the group is selected from one of the following structures:
R 2 the heterocyclic ring of the group is selected from one of the following structures:
3. the 1,3, 4-thiadiazole peptide deformylase inhibitor according to claim 1, wherein the 1,3, 4-thiadiazole peptide deformylase inhibitor is selected from one of the following structures:
4. a process for the preparation of a1, 3, 4-thiadiazole peptide deformylase inhibitor according to any one of claims 1-3, comprising the steps of:
s1: the carboxyl in the compound 1 reacts with hydrazine hydrate under the action of condensing agent CDI to prepare a compound 2;
s2: compound 2 reacts with the carboxyl group in compound a to form compound 3 under the action of condensing agent EDCI, HOBT, NMM;
s3: compound 3 is turned off to form compound 4 under the action of the lawson reagent;
s4: reacting the compound 4 in trifluoroacetic acid and dichloromethane to obtain a compound 5;
s5: condensing the compound 5 with the compound B under the action of HATU and DIPEA to obtain a compound 6;
s6: reacting the compound 6 in trifluoroacetic acid and dichloromethane to obtain a compound 7, namely the 1,3, 4-thiadiazole peptide deformylase inhibitor;
wherein, the preparation route diagram of the 1,3, 4-thiadiazole peptide deformylase inhibitor is shown as follows:
5. the method for producing a1, 3, 4-thiadiazole peptide deformylase inhibitor according to claim 4, wherein,
in the step S1, the mol ratio of the compound 1 to CDI and hydrazine hydrate is 1.0:1.1-2.0:2.0-5.0, the reaction temperature in the step S1 is 0-40 ℃ and the reaction time is 5-24 hours;
in the step S2, the molar ratio of the compound 2 to the compound A, EDCI, HOBT, NMM is 1.0:1.1-1.5:1.0-2.0:1.0-2.0:2.0-5.0, the reaction temperature in the step S2 is 0-40 ℃ and the reaction time is 5-24 hours;
in the step S3, the mol ratio of the compound 3 to the Lawsen reagent is 1.0:1.0-1.5, the reaction temperature in the step S3 is 80-120 ℃, and the reaction time is 1-12 hours;
in the step S4, the molar ratio of the compound 4 to the trifluoroacetic acid is 1.0:5.0-25, the reaction temperature in the step S4 is 0-40 ℃, and the reaction time is 1-10 hours;
in the step S5, the molar ratio of the compound 5 to the compound B, HATU, DIPEA is 1.0:1.1-1.5:1.2-3.0:2.0-5.0, the reaction temperature in the step S5 is 0-40 ℃, and the reaction time is 5-24 hours;
in the step S6, the molar ratio of the compound 6 to the trifluoroacetic acid is 1.0:5.0-25, the reaction temperature in the step S6 is 0-40 ℃, and the reaction time is 1-10 hours.
6. A pharmaceutically acceptable salt or solvate of the 1,3, 4-thiadiazole peptide deformylase inhibitor of any one of claims 1-3.
7. Use of a1, 3, 4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 1-3 in the manufacture of a medicament for inhibiting bacteria.
8. The use according to claim 7, wherein the 1,3, 4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof is used in the manufacture of a medicament for inhibiting drug-resistant bacteria.
9. The use according to claim 8, wherein the 1,3, 4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof is used in the manufacture of a medicament for inhibiting gram positive or gram negative resistant bacteria.
10. The use according to claim 8, wherein the 1,3, 4-thiadiazole peptide deformylase inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof is used in the manufacture of a medicament for inhibiting drug-resistant acinetobacter baumannii.
CN202311693815.8A 2023-12-11 2023-12-11 1,3, 4-thiadiazole peptide deformylase enzyme inhibitor and preparation and application thereof Pending CN117886808A (en)

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