Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors
Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors
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DOI：
10.1016/j.bmc.2012.05.050
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Zhu, Hai-Liang
中科院分区：
文献类型：
--
作者：
Li, Yao;Luo, Yin;Zhu, Hai-Liang
近年来，硝基咪唑及其衍生物因其多样的生物活性而引起了人们的持续关注，最近在药物开发中应用于抗菌化疗药物和抗血管生成缺氧细胞放射增敏剂。为了寻找新的抗菌药物，我们设计并合成了一系列基于恶二唑支架的塞克硝唑类似物（4-21）。其中化合物4和7-21为首次报道。测定了这些化合物对大肠杆菌、铜绿假单胞菌、枯草芽孢杆菌和金黄色葡萄球菌的抑菌活性。这类新的硝基咪唑衍生物具有较强的抗菌活性。大肠杆菌β -酮酰基-酰基载体蛋白合成酶III （FabH）抑制实验和对接模拟表明，2-（2-甲氧基苯基）-5-（（2-甲基-5-硝基- 1h -咪唑-1-基）甲基）-1,3,4-恶二唑（11）和2-（2-甲基-5-硝基- 1h -咪唑-1-基）甲基)-5-（2-甲基苄基）-1,3,4-恶二唑（12）的MIC为1.56-6.25 mu g/mL，是大肠杆菌FabH的最有效抑制剂。(C) 2012 Elsevier Ltd.版权所有。
Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 mu g/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl) methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 mu g/mL were most potent inhibitors of Escherichia coli FabH. (C) 2012 Elsevier Ltd. All rights reserved.