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

Abstract

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 <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 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.

• Authors: 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
• Journal: ACS infectious diseases (ACS Infect Dis) Vol. 2 Issue 6 Pg. 393-8 (06 10 2016) ISSN: 2373-8227 [Electronic] United States
• PMID: 27627627 (Publication Type: Journal Article)

Chemical References

• Antitubercular Agents
• Imidazoles
• Thiazoles

Topics

• Animals
• Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
• Chlorocebus aethiops
• Humans
• Imidazoles (chemistry)
• Molecular Structure
• Mycobacterium tuberculosis (drug effects, genetics, physiology)
• Structure-Activity Relationship
• Thiazoles (chemistry)
• Tuberculosis (drug therapy, microbiology)
• Vero Cells