Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Chemistry : a European Journal
Sydney A VillaumeStéphane P Vincent

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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Citations

Sep 9, 2017·Scientific Reports·Julia S Martin Del CampoPablo Sobrado
Jan 16, 2020·Antibiotics·Zuzana KonyarikováKatarína Mikušová
Feb 11, 2021·Organic & Biomolecular Chemistry·Jian FuStéphane P Vincent
Aug 31, 2019·Biochemistry and Biophysics Reports·Munkhzul GanboldHiroko Isoda
Jun 18, 2020·Bioorganic & Medicinal Chemistry·Carine MaalikiEmilie Thiery
Aug 3, 2021·European Journal of Medicinal Chemistry·Shannon PecnardOlivier Provot
Aug 17, 2021·European Journal of Medicinal Chemistry·Giulia CazzanigaStefania Villa
Sep 25, 2021·Natural Product Research·Anderson Valdiney Gomes RamosDebora Cristina Baldoqui

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