Simplified captopril analogues as NDM-1 inhibitors

Captopril is a New Delhi metallo-beta-lactamase-1 (NDM-1) inhibitor with an IC50 value of 7.9 mu M. It is composed of two units: a 3-mercapto-2-methylpropanoyl fragment and a proline residue. In this study, we synthesized simple amide derivatives of 3-mercapto-2-methylpropanoic acid, and then tested them as NDM-1 inhibitors in order to identify the pharmacophore for NDM-1 inhibition. We found that the lead compound 22 had an IC50 value of 1.0 mu M. Further structure simplification provided compounds 31 and 32, which had IC50 values of 15 and 10 mu M, respectively. As compound 32 is a clinically used antidote for metal poisoning, it has great potential to be repurposed to treat bacterial infections. (c) 2013 Elsevier Ltd. All rights reserved.