Design and development of new class of Mycobacterium tuberculosis L-alanine dehydrogenase inhibitors

Mycobacterium tuberculosis L-alanine dehydrogenase (MTB L-AlaDH) is one of the important drug targets for treating latent/persistent tuberculosis. In this study we used crystal structure of the MTB L-AlaDH bound with cofactor NAD(+) as a structural framework for virtual screening of our in-house database to identified new classes of L-AlaDH inhibitor. We identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitor with IC50 of 9.22 +/- 0.72 mu M. Further lead optimization by synthesis leads to compound 1-(isonicotinamido)-N-2,N-4-bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide (18) with L-AlaDH IC50 of 3.83 +/- 0.12 mu M, 2.0log reduction in nutrient starved dormant MTB model and MIC of 11.81 mu M in actively replicative MTB. (C) 2016 Elsevier Ltd. All rights reserved.