Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity
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- 作者：N. Susantha Chandrasekera ; Torey Alling ; Mai A. Bailey ; Megan Files ; Julie V. Early ; Juliane Ollinger ; Yulia Ovechkina ; Thierry Masquelin ; Prashant V. Desai ; Jeffrey W. Cramer ; Philip A. Hipskind ; Joshua O. Odingo ; Tanya Parish
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：September 24, 2015
- 年：2015
- 卷：58
- 期：18
- 页码：7273-7285
- 全文大小：418K
- ISSN：1520-4804
文摘
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鈥揳ctivity 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.