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

Shaan      Patel; Pradip      Jadav; Rajesh      Bahekar; Kumargurubaran      Nagaswamy; Kasinath      Viswanathan; Purvi      Vyas; Poonam      Giri; S.      Sachchidanand; Mukul      Jain

doi:10.2174/0115701808287192240415062148

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusion: Among tested NCE’s, 4c showed potent MBL inhibitory activity against the VIM-2 enzyme.

Keywords: Antibiotic (Abs), antibiotic resistance, metallo-β-lactamase (MBL) enzymes, 8-thioquinoline (8-TQ), cephalosporin based MBL inhibitors (Cef-MBLi), conjugates, enzyme inhibition.

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DOI https://dx.doi.org/10.2174/0115701808287192240415062148	Print ISSN 1570-1808
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Design and Biological Evaluation of Cephalosporin Based Metallo-β-lactamase (MBL) Inhibitors

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