Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity
Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity
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DOI：
10.1021/acs.jmedchem.5b00546
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发表时间：
2015-09-24
影响因子：
7.3
通讯作者：
Parish, Tanya
中科院分区：
文献类型：
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作者：
Chandrasekera, N. Susantha;Alling, Torey;Parish, Tanya
我们对以2-乙基-1-（3-苯氧基丙基）-1H-苯并[d]咪唑为例的苯氧基烷基苯并咪唑系列化合物的抗结核活性进行了评价。系统地检查了分子的四个片段，以确定与生物活性有关的构效关系。化合物对结核分枝杆菌具有亚微摩尔活性;最有效的化合物具有52 nM的最小抑制浓度（MIC），并且对真核细胞没有细胞毒性（选择性指数= 523）。化合物对M.结核病优于其他细菌物种，包括密切相关的耻垢分枝杆菌。化合物对需氧生长、复制的M.结核病，但对非复制细菌具有杀菌作用。代表性化合物在MDCK细胞中具有中度至高度渗透性，但在啮齿动物和人肝微粒体中快速代谢，表明可能通过氧化代谢介导快速体内肝清除。这些结果表明，容易合成的苯氧烷基苯并咪唑类药物是一类有前途的有效的和选择性的抗结核药物，如果代谢的倾向可以解决。
We conducted an evaluation of the phenoxyalkylbenzimidazole series based on the exemplar 2-ethyl-1-(3-phenoxypropyl)-1H-benzo[d]imidazole for its antitubercular activity. Four segments of the molecule were examined systematically to define a structure activity relationship with respect to biological activity. Compounds had submicromolar activity against Mycobacterium tuberculosis; the most potent compound had a minimum inhibitory concentration (MIC) of 52 nM and was not cytotoxic against eukaryotic cells (selectivity index = 523). Compounds were selective for M. tuberculosis over other bacterial species, including the closely related Mycobacterium smegmatis. Compounds had a bacteriostatic effect against aerobically grown, replicating M. tuberculosis, but were bactericidal against nonreplicating bacteria. Representative compounds had moderate to high permeability in MDCK cells, but were rapidly metabolized in rodents and human liver microsomes, suggesting the possibility of rapid in vivo hepatic clearance mediated by oxidative metabolism. These results indicate that the readily synthesized phenoxyalkylbenzimidazoles are a promising class of potent and selective antitubercular agents, if the metabolic liability can be solved.