Design and Biological Evaluation of Cephalosporin Based Metallo-β-lactamase (MBL) Inhibitors#-Reference-Cited by-同舟云学术

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

Published:2024-04-24 Issue: Volume:21 Page:
ISSN:1570-1808
Container-title:Letters in Drug Design & Discovery
language:en
Short-container-title:LDDD

Author:

Patel Shaan¹²,Jadav Pradip²,Bahekar Rajesh²,Nagaswamy Kumargurubaran²,Viswanathan Kasinath³,Vyas Purvi³,Giri Poonam⁴,S Sachchidanand⁴,Jain Mukul⁵

Affiliation:

1. Cygnus World School, 86W8+CWJ, Motnath Mahadev Mandir Rd, near Motnath Mahadev Temple, Harni, Vadodara, Gujarat, 390022, India

2. Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad, 382210, India

3. Department of Cell Biology, Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad, 382210, India

4. Department of Bioinformatics, Zydus Research Centre, SarkhejBavla N.H. 8A Moraiya, Ahmedabad, 382210, India

5. Department of Pharmacology, Zydus Research Centre, SarkhejBavla N.H. 8A Moraiya, Ahmedabad, 382210, India

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. Method: 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). Result: 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.

Publisher

Bentham Science Publishers Ltd.