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Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors

A compound and application technology, applied in the field of 1-substituted-1H-imidazole-2-carboxylic acid compounds, metallo-β-lactamase inhibitors, can solve the problem of no MBL inhibitors, etc.

Active Publication Date: 2020-05-22
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a large number of MBL inhibitors have been reported, and some inhibitors have shown good in vitro and in vivo activities, so far no MBL inhibitors have been approved for clinical use, and few drugs have entered clinical research

Method used

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  • Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors
  • Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors
  • Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 Synthesis of 1-methyl-1H-imidazole-2-carboxylic acid (compound B):

[0071]

[0072] Dissolve imidazole-2-carboxylic acid ethyl ester 1 (100mg, 0.71mmol) in 10ml THF, slowly add sodium hydride (43mg, 1.78mmol) under ice bath to activate for 1h, then add methyl iodide (507mg, 3.57mmol), the addition is complete, React at room temperature for 1h. The reaction was completed by TLC detection, the reaction was stopped, the solvent was removed by concentration under reduced pressure, dissolved in water, extracted with ethyl acetate (3×20ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purified by column chromatography (PE:EA=1:1) to obtain a yellow oily liquid, namely compound 1-methyl-1H-imidazole-2-carboxylic acid ethyl ester 1b (98mg, yield 89%).

[0073] The compound 1-methyl-1H-imidazole-2-carboxylic acid ethyl ester 1b (98mg, 0.63mmol) was dissolved in 6ml...

Embodiment 2

[0074] Example 2 Synthesis of 1-amino-1H-imidazole-2-carboxylic acid (compound 3):

[0075]

[0076] Dissolve imidazole 2-carboxylic acid (95mg, 0.86mmol) in 10ml N,N-dimethylformamide, add potassium tert-butoxide (154mg, 1.37mmol) under stirring, add O-(4-nitrogen) after activation for 0.5h Benzoyl) hydroxylamine (172 mg, 0.94 mmol). The reaction was performed at room temperature for 10 hours. TLC detected that the reaction was complete. The reaction was stopped. 3N HCl adjusted the Ph to about 5, solids separated out, filtered and washed with dichloromethane to obtain light yellow crystals, namely compound 1-amino-1H-imidazole-2-carboxylic acid ( Namely, compound 3, 82mg, yield 76.6%, HPLC purity>95%). 1 H NMR(400MHz, DMSO-d 6 )δ 7.53 (s, 1H), 7.08 (s, 1H), 6.79 (s, 1H), 6.17 (s br, 2H) ppm. 13 C NMR(101MHz, DMSO-d 6 )δ137.30,126.35,121.75ppm.ESI-MSm / z:128.04[M+H] + .

Embodiment 3

[0077] Example 3 Synthesis of 1-ethyl-1H-imidazole-2-carboxylic acid (compound 4):

[0078]

[0079] Ethyl imidazole-2-carboxylate 1 (100mg, 0.711mmol) was dissolved in 3ml of N,N-dimethylformamide, potassium carbonate (295mg, 21.4mmol) was added for activation for 30 minutes, and ethyl bromide (155mg, 1.41mmol). After the addition, the temperature was raised to 60°C and reacted for 4h. TLC detected that the reaction was complete. The reaction was stopped. Cooled to room temperature, diluted with water, extracted with ethyl acetate (3×20ml), combined the organic layers, washed with saturated brine, and anhydrous Dry over sodium sulfate, filter and concentrate to obtain crude product. Purified by column chromatography (PE:EA=2:1) ​​to obtain a pale yellow liquid, namely compound 1-ethyl-1H-imidazole-2-carboxylic acid ethyl ester 3b (100 mg, yield 83.3%).

[0080] The compound 1-ethyl-1H-imidazole-2-carboxylic acid ethyl ester 3b (100mg, 0.59mmol) was dissolved in 6ml EtOH:H 2 To th...

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Abstract

The invention relates to application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors, and particularly discloses application of compounds shown in a formula I in preparation of metal beta-lactamase inhibitors or antibacterial combined medicines. Experiments prove that the compounds provided by the invention can be used for effectively inhibiting the activity of various MBL enzymes including VIM-2, NDM-1, IMP-1, VIM-1 and VIM-5; the compounds, especially the compounds 11, 13, 14, 29, 30, 34, 37 and 40, have an IC50 value of 2.13 [mu] Mor less on the VIM-2 type MBL enzymes, have a more significant inhibition effect than positive control drugs, and have very good potential in the preparation of MBL enzyme inhibitors. Meanwhile, thecompounds disclosed by the invention are combined with beta-lactam antibiotics, so that metal beta-lactamase generated by drug-resistant bacteria can be effectively inhibited, the antibacterial activity of the antibiotics is enhanced, and the compounds have a very good application prospect in preparation of antibacterial combined medicines.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a 1-substituted-1H-imidazole-2-carboxylic acid compound and its use as a metal β-lactamase inhibitor. Background technique [0002] Beta-lactam antibiotics have the advantages of strong bactericidal activity, low toxicity, wide indications and good clinical efficacy, and they have always occupied a very important position in antibacterial drugs. The most commonly used clinical β-lactam antibiotics mainly include penicillins, cephalosporins, carbapenems, and monocyclic β-lactams. However, in recent years, the resistance of bacteria to these drugs has increased, which has seriously affected the efficacy of these drugs. Serine β-lactamase (SBL) and metal β-lactamase (MBL) produced by pathogenic bacteria can hydrolyze the quaternary β-lactam ring in the chemical structure of antibiotics, destroy the key pharmacophore structure of antibiotics, and make antibiotics Failure is...

Claims

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Application Information

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IPC IPC(8): C07D233/90A61K31/4164C07D405/04C07D403/04C07D409/06A61K31/4178C07D401/06A61K31/4439A61K31/407A61P31/04
CPCC07D233/90C07D405/04C07D403/04C07D409/06C07D401/06A61P31/04A61K31/4164A61K31/4178A61K31/4439A61K31/407A61K2300/00Y02A50/30
Inventor 李国菠王震玲
Owner SICHUAN UNIV
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