Yan Yu-Hang, Chen Jian, Zhan Zhen, Yu Zhu-Jun, Li Gen, Guo Li, Li Guo-Bo, Wu Yong, Zheng Yongxiang
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University Sichuan 610041 China
RSC Adv. 2020 Aug 25;10(52):31377-31384. doi: 10.1039/d0ra06405j. eCollection 2020 Aug 21.
β-Lactam antibiotic resistance mediated by metallo-β-lactamases (MBL) has threatened global public health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the ruthenium-catalyzed meta-selective C-H nitration synthesis method, leading to some -mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors. Here, we described the structure-activity relationship of - and -mercaptopropanamide substituted aryl tetrazoles with clinically relevant MBLs. The resulting most potent compound 13a showed IC values of 0.044 μM, 0.396 μM and 0.71 μM against VIM-2, NDM-1 and IMP-1 MBL, respectively. Crystallographic analysis revealed that 13a chelated to active site zinc ions the thiol group and interacted with the catalytically important residues Asn233 and Tyr67, providing further structural information for the development of thiol based MBL inhibitors.
由金属β-内酰胺酶（MBL）介导的β-内酰胺抗生素耐药性已威胁到全球公共卫生。目前尚无临床可用的MBL抑制剂。我们之前报道了钌催化的间位选择性C-H硝化合成方法，得到了一些巯基丙酰胺取代的芳基四唑作为新型强效MBL抑制剂。在此，我们描述了α-和β-巯基丙酰胺取代的芳基四唑与临床相关MBL的构效关系。所得最有效的化合物13a对VIM-2、NDM-1和IMP-1 MBL的IC值分别为0.044μM、0.396μM和0.71μM。晶体学分析表明，13a通过硫醇基团与活性位点锌离子螯合，并与催化重要残基Asn233和Tyr67相互作用，为基于硫醇的MBL抑制剂的开发提供了进一步的结构信息。
