Jump to main content
Jump to site search

Issue 46, 2012
Previous Article Next Article

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

Author affiliations

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

Back to tab navigation

Supplementary files

Article information


Submitted
04 Sep 2012
Accepted
16 Oct 2012
First published
16 Oct 2012

Org. Biomol. Chem., 2012,10, 9223-9236
Article type
Paper

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

Social activity

Search articles by author

Spotlight

Advertisements