Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Sydney Villaume, Jian Fu, Inès N'Go, Hui Liang, Huayong Lou, Laurent Kremer, Weidong Pan, Stéphane P. Vincent

Research output: Contribution to journalArticle

Abstract

This study reports a novel class of inhibitors of uridine 5′-diphosphate (UDP) galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids are potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed a structure–activity relationship analysis to be performed and which functional groups and structural elements were required for UGM inhibition could be determined. The binding mode of one of the best inhibitors was found to be noncompetitive. Docking simulations indicated that this molecule was likely to bind UGM in its open conformation, in a cavity recently identified as a “druggable” pocket. Importantly, two of the best inhibitors of the M. tuberculosis UGM displayed moderate activity against whole M. tuberculosis cells. This study reports the first natural products that act as inhibitor of UGM. Given the importance of natural products in medicinal chemistry, these results create new opportunities for the discovery of new antitubercular agents.

Original languageEnglish
Pages (from-to)10423-10429
Number of pages7
JournalChemistry - A European Journal
Volume23
Issue number43
DOIs
Publication statusPublished - 1 Aug 2017

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Keywords

  • allosterism
  • enzymes
  • inhibitors
  • natural products
  • structure–activity relationships

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