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. 2013 Jul 11;4(7):675-679.
doi: 10.1021/ml400088y.

Advancement of Imidazo[1,2- a]pyridines with Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium tuberculosis

Garrett C Moraski  1 , Lowell D Markley, Jeffrey Cramer, Philip A Hipskind, Helena Boshoff, Mai Bailey, Torey Alling, Juliane Ollinger, Tanya Parish, Marvin J Miller
Affiliations

Advancement of Imidazo[1,2- a]pyridines with Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium tuberculosis

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

Abstract

A set of fourteen imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of twelve of these agents were ≤ 1 μM against replicating bacteria and five compounds (9, 12, 16, 17 and 18) had MIC values ≤ 0.006 μM. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10 fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities.

Keywords: MDR-TB; Mycobacterium tuberculosis; XDR-TB; imidazo[1,2-a]pyridine-3-carboxamides; pharmacokinetics.

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Figures

Scheme 1
Scheme 1. General Synthesis of Imidazo[1,2-a]pyridine-3-carboxamides
Reagents: (a) ethyl 2-chloroacetoacetate (for 3a–3d) and ethyl 2-chloro-4,4,4-trifluoroacetoacetate (for 3e), DME, reflux, 48 h; (b) (1) LiOH, EtOH, (2) HCl, 56 h; (c) EDC, DMAP, R3, CH3CN, 16 h.
Scheme 2
Scheme 2. Grouping of Imidazo[1,2-a]pyridine Analogues
See this image and copyright information in PMC

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