3-Mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-β-lactamase inhibitors

The production of beta-lactamases is an effective strategy by which pathogenic bacteria can develop resistance against beta-lactam antibiotics. While inhibitors of serine-beta-lactamases are widely used in combination therapy with b-lactam antibiotics, there are no clinically available inhibitors of metallo-beta-lactamases (MBLs), and so there is a need for the development of such inhibitors. This work describes the optimisation of a lead inhibitor previously identified by fragment screening of a compound library. We also report that thiosemicarbazide intermediates in the syntheses of these compounds are also moderately potent inhibitors of the IMP-1 MBL from Pseudomonas aeruginosa. The interactions of these inhibitors with the active site of IMP-1 were examined using in silico methods. (C) 2011 Elsevier Ltd. All rights reserved.