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

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.

SUBMITTER: Moraski GC 

PROVIDER: S-EPMC3733398 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Moraski Garrett C GC   Markley Lowell D LD   Cramer Jeffrey J   Hipskind Philip A PA   Boshoff Helena H   Bailey Mai M   Alling Torey T   Ollinger Juliane J   Parish Tanya T   Miller Marvin J MJ  

ACS medicinal chemistry letters 20130701 7

A set of fourteen imidazo[1,2-<i>a</i>]pyridine-3-carboxamides was synthesized and screened against <i>Mycobacterium tuberculosis</i> H<sub>37</sub>Rv. The minimum inhibitory concentrations of twelve of these agents were ≤ 1 μM against replicating bacteria and five compounds (<b>9, 12, 16, 17</b> and <b>18</b>) had MIC values ≤ 0.006 μM. Compounds <b>13</b> and <b>18</b> were screened against a panel of MDR and XDR drug resistant clinical <i>Mtb</i> strains with the potency of <b>18</b> surpassi  ...[more]

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