Synthesis and enzyme-based evaluation of analogues L-tyrosine thiol carboxylic acid inhibitor of metallo-β-lactamase IMP-1

Journal of Enzyme Inhibition and Medicinal Chemistry

Mahboubeh Kavoosi¹  Hadi Adibi²  Omid Khalili Arjomandi³ 

[1] Department of Biochemistry, Pasteur Institute of Iran, Tehran, Ira;Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran;Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran;The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Australia;

关键词: β-lactam;    β-antibiotic resistance;    metallo-β-lactamase;    inhibitor;    computational modelling;   

DOI  :  10.1080/14756366.2019.1651314

来源: publisher

【 摘 要 】

The emergence of drug-resistant pathogenic bacteria is occurring due to the global overuse and misuse of β-lactam antibiotics. Infections caused by some bacteria which secrete metallo-β-lactamases (enzymes that inactivate β-lactam antibiotics) are increasingly prevalent and have become a major worldwide threat to human health. These bacteria are resistant to β-lactam antibiotics and MBL-inhibitor/β-lactam antibiotic combination therapy can be a strategy to overcome this problem. So far, no clinically available inhibitors of metallo-β-lactamases (MBLs) have been reported. In this study, L-benzyl tyrosine thiol carboxylic acid analogues (2a–2k) were synthesized after the study of computational simulation by adding of methyl, chloro, bromo and nitro groups to the benzyl ring for investigation of SAR analysis. Although the synthesized molecules 2a–k shows the potent inhibitory effects against metallo-β-lactamase (IMP-1) with the range of Kic values of 1.04–4.77 µM, they are not as potent as the candidate inhibitor.

【 授权许可】

CC BY