5 years ago

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors
Jian Fu, Laurent Kremer, Hui Liang, Sydney A. Villaume, Weidong Pan, Stéphane P. Vincent, Huayong Lou, Inès N'Go
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. Tolerable modifications: A series of natural molecules are potent inhibitors of the uridine 5′-diphosphate (UDP) galactopyranose mutase (UGM) of Mycobacterium tuberculosis. Methylated analogues were prepared and docking calculations allowed a structure–activity relationship study to be performed (see scheme). Two of the best flavonoid inhibitors exhibited inhibition against the whole Mycobacterium tuberculosis bacteria.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701812

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