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Issue 46, 2012
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Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site

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Abstract

Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro.

Graphical abstract: Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site

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Publication details

The article was received on 04 Sep 2012, accepted on 16 Oct 2012 and first published on 16 Oct 2012


Article type: Paper
DOI: 10.1039/C2OB26736E
Org. Biomol. Chem., 2012,10, 9223-9236

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    Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site

    A. Manos-Turvey, K. M. Cergol, N. K. Salam, E. M. M. Bulloch, G. Chi, A. Pang, W. J. Britton, N. P. West, E. N. Baker, J. S. Lott and R. J. Payne, Org. Biomol. Chem., 2012, 10, 9223
    DOI: 10.1039/C2OB26736E

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