First identification of isatin-β-thiosemicarbazones as novel inhibitors of New Delhi metallo-β-lactamase-1: Chemical synthesis, biological evaluation and molecular simulation

New Delhi metallo-beta-lactmase-1 (NDM-1) catalyzes the hydrolysis of beta-lactam antibiotics and cleaves the p-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak NDM-1 inhibitor, with an IC50 of 297.6 mu mol/L. Based on this result, a series of isatin-beta-thiosemicarbazones (IBTs) were synthesized and biologically evaluated as novel NDM-1 inhibitors. Nine of the IBT compounds showed IC50 values of <10 mu mol/L, the best of which was 2.72 mu mol/L. Comparative field analysis (CoMFA) contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of NDM-1 inhibitors. (C) 2017 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.