Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity

• Published in: ACS medicinal chemistry letters 2011-06, Vol.2 (6), p.466-470
• Main Authors: Moraski, Garrett C, Markley, Lowell D, Hipskind, Philip A, Boshoff, Helena, Cho, Sanghyun, Franzblau, Scott G, Miller, Marvin J
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml200036r

A set of nine 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides and one 2,6-dimethylimidazo[1,2-a]pyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro antituberculosis activity versus replicating, nonreplicating, multi- and extensive drug resistant Mtb strains. The MIC90 values of seven of these agents were ≤1 μM against the various tuberculosis strains tested. A representative compound of this class (1) was screened against seven nontubercular strains as well as other nonmycobacteria organisms and demonstrated remarkable microbe selectivity. A transcriptional profiling experiment of Mtb treated with compound 1 was performed to give a preliminary indication of the mode of action. Lastly, the in vivo ADME properties of compounds 1, 3, 4, and 6 were assessed. The 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides are a druglike and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics.