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

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langueAnglais
Pages10423-10429
Nombre de pages7
journalChemistry - A European Journal
Volume23
Numéro43
Les DOIs
étatPublié - 1 août 2017

Empreinte digitale

Flavonoids
UDP-galactopyranose mutase
Biological Products
Enzymes
Intramolecular Transferases
Antitubercular Agents
Diphosphates
Uridine
Biosynthesis
Galactose
Functional groups
Conformations
Screening
Cells
Molecules
Pharmaceutical Chemistry

mots-clés

    Citer ceci

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    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.",
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    Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors. / Villaume, Sydney; Fu, Jian; N'Go, Inès; Liang, Hui; Lou, Huayong; Kremer, Laurent; Pan, Weidong; Vincent, Stéphane P.

    Dans: Chemistry - A European Journal, Vol 23, Numéro 43, 01.08.2017, p. 10423-10429.

    Résultats de recherche: Contribution à un journal/une revueArticle

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    AU - Lou,Huayong

    AU - Kremer,Laurent

    AU - Pan,Weidong

    AU - Vincent,Stéphane P.

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