Advancement of Imidazo[1,2‑a]pyridines with Improved Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis

A set of 14 imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of 12 of these agents were ≤1 μM against replicating bacteria and 5 compounds (9, 12, 16, 17, and 18) had MIC values ≤0.006 μM. Compounds 13...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2013-07, Vol.4 (7), p.675-679
Main Authors: Moraski, Garrett C, Markley, Lowell D, Cramer, Jeffrey, Hipskind, Philip A, Boshoff, Helena, Bailey, Mai A, Alling, Torey, Ollinger, Juliane, Parish, Tanya, Miller, Marvin J
Format: Article
Language:English
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Letter
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Summary:A set of 14 imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of 12 of these agents were ≤1 μM against replicating bacteria and 5 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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml400088y