Title

Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles as potent metallo-β-lactamase inhibitors

Document Type

Article

Abstract

Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-β-lactamases (MBLs), using Klebsiella pneumoniae NDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5–16.4 µM) against NDM-1, IMP-1 and AIM-1 MBLs. Furthermore, all compounds showed promising antibacterial activity against (K+, K1-K9) resistant clinical isolates of K. pneumoniae and were able to re-sensitize resistant K. pneumoniae (K5) strain towards meropenem and cefalexin. Besides, in vivo toxicity testing exhibited that the most active compound was non-toxic and well tolerated by the experimental animals orally up to 350 mg/kg and up to 125 mg/kg parenterally. The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Generally, this work presents a fruitful matrix to extend the chemical space for MBLs inhibition. This aids in tackling drug-resistance issues in antibacterial treatment.

Publication Date

12-1-2020

Faculty

Faculty of Applied Health Sciences Technology

Subject Area

Life Sciences, Biochemistry, Genetics, Molecular Biology, Pharmaceutical Science, Pharmacology, Toxicology

Indexed in Scopus

yes

Indexed in Web Of Science

yes

DOI

https://doi.org/10.1016/j.bioorg.2020.104386

Volume

105

Keywords

AIM-1, Docking, IMP-1, Inhibition assay, K. pneumonia, Liposome, MBLs, NDM-1, Pyrazoles, Sulfonyl hydrazones

ISSN

00452068

eISSN

10902120

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