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Identification of 2-Aminothiazole-4-Carboxylate derivatives active against mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH

Al-Balas, Qosay and Anthony, Nahoum G. and Al-Jaidi, Bilal and Alnimr, Amani and Abbott, Grainne and Brown, Alistair K. and Taylor, Rebecca C. and Besra, Gurdyal S. and McHugh, Timothy D. and Gillespie, Stephen H. and Johnston, Blair F. and Mackay, Simon P. and Coxon, Geoffrey D. (2009) Identification of 2-Aminothiazole-4-Carboxylate derivatives active against mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH. PLoS One, 4 (5). ISSN 1932-6203

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Abstract

Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents.