Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Al-Balas, Qosay, Anthony, Nahoum, Al-Jaidi, Bilal, Alnimr, Amani, Abbott, Grainne, Brown, Alistair, Taylor, Rebecca, Besra, Gurdyal, McHugh, Timothy, Gillespie, Stephen, Johnston, Blair, Mackay, Simon and Coxon, Geoffrey (2009) Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH. PLoS ONE, 4 (5). e5617. ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0005617

Abstract

Background
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.

Methodology/Principal Findings
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-carboxylateinhibited 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.

Conclusions/Significance
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.

Item Type: Article
Additional Information: Available under the Creative Commons Attribution License 2.5
Uncontrolled Keywords: mycobacterium tuberculosis
Subjects: A100 Pre-clinical Medicine
C900 Others in Biological Sciences
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: EPrint Services
Date Deposited: 11 May 2010 09:10
Last Modified: 29 Oct 2017 17:35
URI: http://nrl.northumbria.ac.uk/id/eprint/1040

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