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

Saleh, Neveen M.; Moemen, Yasmine S.; Mohamed, Sara H.; Fathy, Ghady; Ahmed, Abdullah A. S.; Al-Ghamdi, Ahmed A.; Ullah, Sami; El Sayed, Ibrahim El-Tantawy

doi:10.3390/antibiotics11010053

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

^1,*

²,

³,

⁴

^5,6

and

Ibrahim El-Tantawy El Sayed

^3,*

Department of Microbiology, National Organization for Drug Control and Research, Giza 12553, Egypt

Clinical Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt

Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt

⁴

Department of Physics, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

⁵

Research Center for Advanced Materials Science (RCAMS), King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia

⁶

Department of Chemistry, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia

Authors to whom correspondence should be addressed.

Academic Editors: Helena Felgueiras and Jean-Marc Sabatier

Antibiotics 2022, 11(1), 53; https://doi.org/10.3390/antibiotics11010053

Received: 15 October 2021 / Revised: 28 December 2021 / Accepted: 29 December 2021 / Published: 1 January 2022

(This article belongs to the Special Issue New Biomolecules and Drug Delivery Systems as Alternatives to Conventional Antibiotics)

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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 (1a–e and 2a–e) as DNA gyrase inhibitors. The synthesized compounds were screened for their activity (antibacterial and DNA gyrase inhibition) against ciprofloxacin-resistant E.coli and Klebsiella pneumoniae clinical isolates having mutations (deletion and substitution) in QRDR region of DNA gyrase. The target compound (2a) that exhibited the most potent activity against ciprofloxacin Gram-negative clinical isolates was selected to screen its inhibitory activity against DNA gyrase displayed IC₅₀ of 12.03 µM. In addition, a docking study was performed with inhibitor (2a), 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 (2a) to DNA gyrase is mediated and modulated by divalent Mg²⁺ 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. View Full-Text

Keywords: cyclic diphenylphosphonate; quinoline; antibacterial activity; DNA gyrase inhibitor; molecular docking; magnesium ion

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Saleh, N.M.; Moemen, Y.S.; Mohamed, S.H.; Fathy, G.; Ahmed, A.A.S.; Al-Ghamdi, A.A.; Ullah, S.; El Sayed, I.E.-T. Experimental and Molecular Docking Studies of Cyclic Diphenyl Phosphonates as DNA Gyrase Inhibitors for Fluoroquinolone-Resistant Pathogens. Antibiotics 2022, 11, 53. https://doi.org/10.3390/antibiotics11010053

AMA Style

Saleh NM, Moemen YS, Mohamed SH, Fathy G, Ahmed AAS, Al-Ghamdi AA, Ullah S, El Sayed IE-T. Experimental and Molecular Docking Studies of Cyclic Diphenyl Phosphonates as DNA Gyrase Inhibitors for Fluoroquinolone-Resistant Pathogens. Antibiotics. 2022; 11(1):53. https://doi.org/10.3390/antibiotics11010053

Chicago/Turabian Style

Saleh, Neveen M., Yasmine S. Moemen, Sara H. Mohamed, Ghady Fathy, Abdullah A.S. Ahmed, Ahmed A. Al-Ghamdi, Sami Ullah, and Ibrahim E.-T. El Sayed. 2022. "Experimental and Molecular Docking Studies of Cyclic Diphenyl Phosphonates as DNA Gyrase Inhibitors for Fluoroquinolone-Resistant Pathogens" Antibiotics 11, no. 1: 53. https://doi.org/10.3390/antibiotics11010053

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

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