Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

This study reports a novel class of inhibitors of 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 were found to be potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed to perform a structure-activity relationship analysis and to determine which functional groups and structural elements are required for UGM inhibition.The binding mode of one of the best inhibitor was found to be non-competitive. Docking simulations indicated that this molecule likely binds UGM in its open conformation, in a cavity recently identified as "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 acting as inhibitors of UGM. Given the importance of natural products in medicinal chemistry, these results create new opportunities for the discovery of new antitubercular agents.