| Summary: | Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC<sub>50</sub> value range of 0.032–15.64 μM except <b>7</b>. The chlorine substituted compounds (<b>1</b>, <b>2</b> and <b>3</b>) inhibited NDM-1 with an IC<sub>50</sub> value of less than 0.96 μM, and the fluorine substituted <b>12</b> and <b>13</b> inhibited VIM-2 with IC<sub>50</sub> 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 <b>9</b> and <b>13</b> are mixed inhibitors for ImiS with <i>K</i><sub>i</sub> values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that <b>1</b> and <b>9</b>, 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.
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