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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Antimicrobial activity of amphipathic alpha,alpha-disubstituted beta-amino amide derivatives against ESBL - CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character
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Antimicrobial activity of amphipathic alpha,alpha-disubstituted beta-amino amide derivatives against ESBL - CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character

机译：Amphipathicα，α-二取代的β-氨基酰胺衍生物对ESBL - Carba产生多种抗菌细菌的抗菌活性; 卤化，亲脂性和阳离子特征的影响

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The rapid emergence and spread of multi-resistant bacteria have created an urgent need for new antimicrobial agents. We report here a series of amphipathic alpha,alpha-disubstituted beta-amino amide derivatives with activity against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum beta-lactamase - carbapenemase (ESBL-CARBA) production. A variety of halogenated aromatic side-chains were investigated to improve antimicrobial potency and minimize formation of Phase I metabolites. Net positive charge and cationic character of the derivatives had an important effect on toxicity against human cell lines. The most potent and selective derivative was the diguanidine derivative 4e with 3,5-di-brominated benzylic side-chains. Derivative 4e displayed minimum inhibitory concentrations (MIC) of 0.25-8 mu g/mL against Gram-positive and Gram-negative reference strains, and 2-32 mu g/mL against multi-resistant clinical isolates. Derivative 4e showed also low toxicity against human red blood cells (EC50 > 200 pg/mL), human hepatocyte carcinoma cells (HepG2: EC50>64 mu g/mL), and human lung fibroblast cells (MRC-5: EC50 > 64 mu g/mL). The broad-spectrum antimicrobial activity and low toxicity of diguanylated derivatives such as 4e make them attractive as lead compounds for development of novel antimicrobial drugs. (C) 2019 The Authors. Published by Elsevier Masson SAS.
机译：多种抗菌的快速出现和传播迫切需要新的抗微生物剂。我们在此报道一系列的Amphipathtα，α-二取代的β-氨基酰胺衍生物，其具有针对30个多抗革兰氏阳性和革兰氏阴性细菌的多种多种临床分离物的活性，包括与扩展谱β-内酰胺酶 - 碳癌酶（ESBL-Carba）的分离物（ESBL-Carba ） 生产。研究了各种卤代芳族侧链，以改善抗微生物效力并最小化形成I相代谢物的形成。衍生物的净正电荷和阳离子特征对对人细胞系的毒性有重要作用。最有效和选择性衍生物是二胍衍生物4e，具有3,5-二溴化苄基侧链。衍生物4e针对革兰氏阳性和革兰氏阴性参考菌株显示0.25-8μg/ ml的最小抑制浓度（MIC），以及针对多种抗性临床分离株2-32μg/ ml。衍生物4e对人红细胞（EC50> 200 pg / ml），人肝细胞癌细胞（HepG2：EC50>64μg/ ml）和人肺成纤维细胞（MRC-5：EC50>64μm g / ml）。 Diguantylated衍生物的广谱抗微生物活性和低毒性如4e使它们作为新型抗微生物药物的铅化合物具有吸引力。 （c）2019年作者。由Elsevier Masson SA出版。

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