Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-ß-Lactamase Inhibitors.

Metallo-ß-lactamases (MßLs) are the target enzymes of ß-lactam antibiotic resistance, and there are no effective inhibitors against MßLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MßLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC50 value range of 0.032⁻15.64 µM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC50 value of less than 0.96 µM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC50 values of 38.9 and 2.8 µM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with Ki values of 0.074 and 0.27µM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.