College of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, China.
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, China.
Molecules. 2019 Mar 25;24(6):1174. doi: 10.3390/molecules24061174.
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 value range of 0.032⁻15.64 μM except . The chlorine substituted compounds (, and ) inhibited NDM-1 with an IC value of less than 0.96 μM, and the fluorine substituted and inhibited VIM-2 with IC 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 and are mixed inhibitors for ImiS with values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that and , 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.
金属β-内酰胺酶（MβLs）是β-内酰胺类抗生素耐药性的靶酶，迄今为止，临床上还没有针对 MβLs 的有效抑制剂。在本研究中，设计并合成了 13 种卤代三唑硫代乙酰胺作为 MβLs 抑制剂的有效骨架。除 外，所有化合物均显示出对 ImiS 的抑制活性，IC 值范围为 0.032⁻15.64 μM。氯取代化合物（、和）对 NDM-1 的抑制作用的 IC 值均小于 0.96 μM，氟取代化合物 和 对 VIM-2 的抑制作用的 IC 值分别为 38.9 和 2.8 μM。然而，在抑制剂浓度高达 1 mM 的情况下，没有一种三唑硫代乙酰胺对 L1 表现出活性。酶抑制动力学研究表明，化合物 和 是 ImiS 的混合抑制剂，以亚胺培南为底物时， 值分别为 0.074 和 0.27μM。对接研究表明，对 ImiS 抑制活性最高的化合物 和 ，通过三唑基团桥接 ASP120 和羟基桥接 ASN233 与 CphA 的结合位点稳定相互作用，可作为 ImiS 的替代物结合。
