1,2,4-Triazole-3-thione compounds as inhibitors of di-zinc metallo-β-lactamases

Metallo-β-lactamases (MBL) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We have previously identified the original binding mode of a 4-amino-1,2,4-triazole-3-thione compound, IIIA, within the di-zinc active site of the L1 MBL. Here, we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB. Unexpectedly, IIIB showed a similar but reverse binding mode compared to IIIA. These 3D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of di-zinc metallo-enzymes. Based on these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the μM range towards at least one of five representative MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2 and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial di-nuclear Zn-dependent hydrolases belonging to the MBL fold superfamily (i.e. endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. While the bacterial tRNases were not inhibited, the best IC50's towards plasmodial glyoxalase II were in the 10 μM range.