Design and Biological Evaluation of Cephalosporin Based Metallo-β-lactamase (MBL) Inhibitors#

Prevalence of microbial resistance due to Metallo-β-lactamase (MBL) enzyme pose a serious threat to human life. MBLs depend on active site zinc for their hydrolytic activity; hence, the investigation of zinc chelators emerged as an attractive strategy for the development of potent MBL inhibitors. To prove that such chelators selectively target MBLs, in the present investigation, novel cephalosporins based MBL inhibitors (Cef-MBLi) were designed as a conjugate of cephalosporins with a potent zinc binder 8-thioquinoline (8-TQ). Cef-MBLi showed site specific release of conjugate only in the presence of a Veronaintegron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme through hydrolytic cleavage mechanism. A total of 6 (4a-e and 6f) New Chemical Entities (NCE’s) were prepared, characterized and subjected for in vitro study. Among tested NCE’s, 4c showed potent MBL inhibitory activity against the VIM-2 enzyme.