Discovery of mercaptopropanamide-substituted aryl tetrazoles as new broad-spectrum metallo-beta-lactamase inhibitors

beta-Lactam antibiotic resistance mediated by metallo-beta-lactamases (MBL) has threatened global public health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the ruthenium-catalyzed meta-selective C-H nitration synthesis method, leading to somemeta-mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors. Here, we described the structure-activity relationship ofmeta- andortho-mercaptopropanamide substituted aryl tetrazoles with clinically relevant MBLs. The resulting most potent compound13ashowed IC(50)values of 0.044 mu M, 0.396 mu M and 0.71 mu M against VIM-2, NDM-1 and IMP-1 MBL, respectively. Crystallographic analysis revealed that13achelated to active site zinc ionsviathe thiol group and interacted with the catalytically important residues Asn233 and Tyr67, providing further structural information for the development of thiol based MBL inhibitors.