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Issue 5, 2012
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Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosisglutamine synthetase inhibitors

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Abstract

Based on an imidazo[1,2-a]pyridine hit from a high-throughput screening directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a number of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 μM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified with single-digit micromolar potency and one with sub-micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize many of the structure–activity relationships observed.

Graphical abstract: Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosis glutamine synthetase inhibitors

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Publication details

The article was received on 20 Dec 2011, accepted on 03 Mar 2012 and first published on 12 Mar 2012


Article type: Concise Article
DOI: 10.1039/C2MD00310D
Med. Chem. Commun., 2012,3, 620-626

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    Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosis glutamine synthetase inhibitors

    A. Nordqvist, M. T. Nilsson, O. Lagerlund, D. Muthas, J. Gising, S. Yahiaoui, L. R. Odell, B. R. Srinivasa, M. Larhed, S. L. Mowbray and A. Karlén, Med. Chem. Commun., 2012, 3, 620
    DOI: 10.1039/C2MD00310D

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