Article (Scientific journals)
Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site
Manos-Turvey, Alexandra; Cergol, Katie M.; Salam, Noeris K. et al.
2012In Organic and Biomolecular Chemistry, 10 (46), p. 9223-9236
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Abstract :
[en] 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.
Disciplines :
Pharmacy, pharmacology & toxicology
Chemistry
Biochemistry, biophysics & molecular biology
Author, co-author :
Manos-Turvey, Alexandra ;  University of Sydney > School of Chemistry
Cergol, Katie M.
Salam, Noeris K.
Bulloch, Esther M. M.
Chi, Gamma
Pang, Angel
Britton, Warwick J.
West, Nicholas P.
Baker, Edward N.
Lott, J. Shaun
Payne, Richard J.
Language :
English
Title :
Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site
Publication date :
2012
Journal title :
Organic and Biomolecular Chemistry
ISSN :
1477-0520
eISSN :
1477-0539
Publisher :
Royal Society of Chemistry, Cambridge, United Kingdom
Volume :
10
Issue :
46
Pages :
9223-9236
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 03 June 2016

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