332909-36-1Relevant academic research and scientific papers
Halogen-substituted triazolethioacetamides as a potent skeleton for the development of metallo-β-lactamase inhibitors
Zhang, Yilin,Yan, Yong,Liang, Lufan,Jiefeng,Wang, Xuejun,Li, Li,Yang, Kewu
, (2019)
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 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.
