Experimental and Molecular Docking Studies of Cyclic Diphenyl Phosphonates As DNA Gyrase Inhibitors for Fluoroquinolone-Resistant Pathogens

Overview

Journal Antibiotics (Basel)

Specialty Pharmacology

Date 2022 Jan 21

PMID 35052930

Authors

Neveen M Saleh

Yasmine S Moemen

Sara H Mohamed

Ghady Fathy

Abdullah A S Ahmed

Ahmed A Al-Ghamdi

Sami Ullah

Ibrahim El-Tantawy El Sayed

Affiliations

Soon will be listed here.

Abstract

DNA gyrase and topoisomerase IV are proven to be validated targets in the design of novel antibacterial drugs. In this study, we report the antibacterial evaluation and molecular docking studies of previously synthesized two series of cyclic diphenylphosphonates (- and -) as DNA gyrase inhibitors. The synthesized compounds were screened for their activity (antibacterial and DNA gyrase inhibition) against ciprofloxacin-resistant and clinical isolates having mutations (deletion and substitution) in QRDR region of DNA gyrase. The target compound () that exhibited the most potent activity against ciprofloxacin Gram-negative clinical isolates was selected to screen its inhibitory activity against DNA gyrase displayed IC of 12.03 µM. In addition, a docking study was performed with inhibitor (), to illustrate its binding mode in the active site of DNA gyrase and the results were compatible with the observed inhibitory potency. Furthermore, the docking study revealed that the binding of inhibitor () to DNA gyrase is mediated and modulated by divalent Mg at good binding energy (-9.08 Kcal/mol). Moreover, structure-activity relationships (SARs) demonstrated that the combination of hydrazinyl moiety in conjunction with the cyclic diphenylphosphonate based scaffold resulted in an optimized molecule that inhibited the bacterial DNA gyrase by its detectable effect in vitro on gyrase-catalyzed DNA supercoiling activity.

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