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Use of proline derivatives in the preparation of β-lactamase inhibitors

A technology of lactamase and derivatives, which is applied in the field of proline derivatives in the preparation of β-lactamase inhibitors, can solve the problems of metal β-lactams that are not suitable for inhibiting super drug-resistant bacteria, unpleasant smell of drugs, and drug toxicity. Side effects and other issues, to achieve the effect of treating drug-resistant bacterial infections, good drug application prospects, and alleviating drug resistance

Inactive Publication Date: 2020-02-07
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the above-mentioned marketed drugs or compounds that have an inhibitory effect on NDM-1 contain sulfhydryl molecular structures in their molecular structures. The ability to make thiol-containing compounds used as drugs will have non-selective inhibitory effects on various metal ion-containing enzymes in the human body, resulting in drug toxicity and side effects
For example, if figure 1 Most of the thiol-containing drugs summarized and reported by Proschak are considered unsuitable as clinical drugs for inhibiting metallo-β-lactamase NDM-1 of super-drug-resistant bacteria (J.Med.Chem.2015,58,3626-3630)

Method used

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  • Use of proline derivatives in the preparation of β-lactamase inhibitors
  • Use of proline derivatives in the preparation of β-lactamase inhibitors
  • Use of proline derivatives in the preparation of β-lactamase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the synthesis of compound Ia:

[0031]

[0032](1) Dissolve o-carboxyphenylacetic acid (360mg, 2mmol) in dry dimethylformamide solution (10ml) at room temperature, and add ethyl[3-(dimethylamino)propyl]carbodiol successively Imine (384mg, 2mmol) and 1-hydroxybenzotriazole (270mg, 2mmol), stirred for 15 minutes, then added L-proline benzyl ester hydrochloride (532mg, 2.2mmol) and 4-dimethylaminopyridine (805mg, 6.6mmol), the reaction solution was reacted at room temperature for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, the reactant was diluted with dichloromethane, washed with saturated sodium bicarbonate, 3M hydrochloric acid solution and saturated sodium chloride solution respectively, and the organic phase solvent was dried with anhydrous sodium sulfate and spin-dried under reduced pressure. , the reaction product was purified by HPLC (methanol: water = 7: 3) to obtain a white solid intermediate (404 m...

Embodiment 2

[0034] Embodiment 2: the synthesis of compound Ib

[0035]

[0036] (1) Dissolve o-carboxybenzenesulfonic acid (360mg) in dry dimethylformamide solution (10ml) at room temperature, and add ethyl[3-(dimethylamino)propyl]carbodiethylene Amine (384mg) and 1-hydroxybenzotriazole (270mg), stirred for 15 minutes, then added L-proline benzyl ester hydrochloride (532mg) and 4-dimethylaminopyridine (805mg), the reaction solution was at room temperature The reaction was carried out for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, the reactant was diluted with dichloromethane, washed with saturated brine, 3M hydrochloric acid solution and saturated sodium chloride solution respectively, and the organic phase solvent was dried with anhydrous sodium sulfate, spin-dried under reduced pressure, and washed with The reaction product was purified by HPLC (methanol:water=5:5) to obtain a white solid product (404 mg), which was directly used in th...

Embodiment 3

[0038] Embodiment 3: the synthesis of compound Ic, Id

[0039]

[0040] (1) At room temperature, add o-sulfonamide benzoic acid (50mg, 0.25mmol) in thionyl chloride (3ml) in the reaction flask, raise the temperature of the system to reflux, react for 2 hours, remove thionyl chloride under low pressure, Dissolve the residue in dry dichloromethane, add it to a solution of L-proline benzyl ester hydrochloride (60mg, 0.25mmol) in dry dichloromethane at 0°C, and then add triethylamine (56mg, 0.55mmol), the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reactant was diluted with dichloromethane, washed with saturated sodium bicarbonate and saturated sodium chloride solution respectively, and the organic phase solvent was dried with anhydrous sodium sulfate, spin-dried under reduced pressure, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate=2:1) ​​to purify the reaction product to obtain the ta...

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Abstract

The invention discloses use of a proline derivative in preparation of beta-lactamase inhibitors, and the proline derivative is represented by formula (I), wherein the amide bond in the formula (I) comprises a naturally occurring cis or trans rotamer; R1 is OH or NH2; R2 is o-sulfophenyl, o-sulphonylaminophenyl, m-sulfophenyl, m-sulfonamidophenyl, p-sulfophenyl, p-sulfonamidophenyl, or o-carboxybenzyl. Activity tests show that the proline derivative represented by the formula (I) has a good inhibitory effect on beta-lactamase, especially on NDM-1. By inhibiting of the activity of the beta-lactamase, especially the NDM-1, hydrolysis of beta-lactam antibiotics by the NDM-1 can be reduced or even eliminated, drug resistance caused by the NDM-1 can be alleviated, the curative effect of the antibiotics on bacteria can be restored, and drug-resistant bacterial infections caused by the NDM-1 can be treated.

Description

technical field [0001] The present invention relates to the use of proline derivatives in the preparation of β-lactamase inhibitors. Background technique [0002] Since the clinical application of antibiotics in the 1940s, the morbidity and mortality of human infectious diseases have been significantly improved and increased. However, with the abuse and misuse of antibiotics by humans, most pathogenic bacteria have transformed into antibiotic-resistant bacteria. Therefore, it is urgent to suppress the drug resistance of pathogenic bacteria and restore the efficacy of antibacterial drugs. [0003] On August 11, 2010, the famous medical journal "The Lancet" published an article reporting a case of a special Enterobacteriaceae bacteria resistant to all β-lactam antibacterial drugs. The report has attracted worldwide attention. In-depth studies have found that this type of bacteria carries a new type of metallo-β-lactamase encoded by Klebsiella pneumoniae (KlebsiellapneμMoniae)...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/401A61P31/04
CPCA61K31/401
Inventor 高清志刘欣雨马玉茹
Owner TIANJIN UNIV
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