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

ACS infectious diseases, Volume: 2, Issue: 6
June 10, 2016
Garrett C Moraski GC, Natalie Seeger N, Patricia A Miller PA, Allen G Oliver AG, Helena I Boshoff HI, Sanghyun Cho S, Surafel Mulugeta S, Jeffery R Anderson JR, Scott G Franzblau SG, Marvin J Miller MJ

Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-a]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-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant Mycobacterium tuberculosis (Mtb) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values 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 bd 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 Mtb.