1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-β-Lactamase Inhibitors

Metallo-β-lactamases (MBLs) are increasingly involved as a
major mechanism of resistance to carbapenems in relevant
opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical
need. We previously reported several series of compounds
based on the 1,2,4-triazole-3-thione scaffold. In particular, Schiff
bases formed between diversely 5-substituted-4-amino com pounds and 2-carboxybenzaldehyde were broad-spectrum
inhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately,
these compounds were unable to restore antibiotic suscepti bility of MBL-producing bacteria, probably because of poor
penetration and/or susceptibility to hydrolysis. To improve their
microbiological activity, we synthesized and characterized
compounds where the hydrazone-like bond of the Schiff base
analogues was replaced by a stable ethyl link. This small change
resulted in a narrower inhibition spectrum, as all compounds
were poorly or not inhibiting NDM-1 and IMP-1, but showed a
significantly better activity on VIM-type enzymes, with Ki values
in the μM to sub-μM range. The resolution of the crystallo graphic structure of VIM-2 in complex with one of the best
inhibitors yielded valuable information about their binding
mode. Interestingly, several compounds were shown to restore
the β-lactam susceptibility of VIM-type-producing E. coli labo ratory strains and also of K. pneumoniae clinical isolates. In
addition, selected compounds were found to be devoid of
toxicity toward human cancer cells at high concentration, thus
showing promising safety.