Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB

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• 作者：Garrett C. Moraski ; Natalie Seeger ; Patricia A. Miller ; Allen G. Oliver ; Helena I. Boshoff ; Sanghyun Cho ; Surafel Mulugeta ; Jeffery R. Anderson ; Scott G. Franzblau ; Marvin J. Miller
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：June 10, 2016
• 年：2016
• 卷：2
• 期：6
• 页码：393-398
• 全文大小：369K
• ISSN：2373-8227

文摘

Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-<i>ai>]pyridine-3-carboxamides encouraged extended structure–activity relationship studies of additional scaffolds. This study reports on the in vitro profiling of the imidazo[2,1-<i>bi>]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant <i><i>Mycobacterium tuberculosisi>i> (<i>Mtbi>) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values <10 nM and toxicity >100 μM. On-target selectivity of this series was confirmed by cross-resistance of specific QcrB mutants as well as the hypersusceptibility of a mutant with a functional gene deletion of the alternative cytochrome <i>bdi> oxidase. Additionally, to demonstrate selectivity, three analogues (6, 15, 17) were broadly screened against a diverse set of eight strains of bacteria, including both Gram-positive and Gram-negative as well as six disease-causing non-tuberculosis mycobacteria. Finally, compounds 16 and 17 were found to be active in macrophages infected with <i>Mtbi>.