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. 2011 Jun 9;2(6):466-470.
doi: 10.1021/ml200036r.

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

Garrett C Moraski  1 , Lowell D Markley, Philip A Hipskind, Helena Boshoff, Sanghyun Cho, Scott G Franzblau, Marvin J Miller
Affiliations

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

Garrett C Moraski et al. ACS Med Chem Lett. .

Abstract

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 anti-tuberculosis activity versus replicating, non-replicating, multi- and extensive drug resistant Mtb strains. The MIC(90) 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 non-tubercular strains as well as other non-mycobacteria 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 drug-like and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics.

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Figures

Scheme 1
Scheme 1. Synthesis of Imidazo[1,2-a]pyridines
Reagents: (a) Ethyl 2-chloroacetoacetate, DME, reflux, 48 h. (b) (1) LiOH, EtOH; (2) HCl, 56 h. (c) EDC, DMAP, R1, ACN, 16 h.
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