Drug Repurposing Approach in Developing New Furosemide Analogs as Antimicrobial Candidates and Anti-PBP: Design, Synthesis, and Molecular Docking.

Autor: Harras MF; Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt., Sabour R; Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt., Farghaly TA; Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah 24230, Saudi Arabia., Ibrahim MH; Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Aug; Vol. 137, pp. 106585. Date of Electronic Publication: 2023 May 06.
DOI: 10.1016/j.bioorg.2023.106585
Abstrakt: Multidrug-resistant microorganisms have become a global health problem, prompting research into new antimicrobials. Drug repurposing is a new technique in drug discovery used to improve drug development success. As a well-studied medication with a sulfonamide moiety, furosemide was chosen to study its antimicrobial effect on different microbial strains. In addition, a new family of furosemide analogs was investigated for their antimicrobial efficacy. According to the obtained results, the majority of the examined molecules exhibited potential antimicrobial activity. Compounds 3b and 4a had the best anti-MRSA results, with an MIC = 7.81 µg/mL. They also demonstrated potent anti-gram-negative activity against E. coli (MIC = 1.95 µg/mL and 3.91 µg/mL, respectively). A time-killing kinetics study against E. coli and MRSA showed bactericidal actions of 3b and 4a within 120-150 min. Moreover, an anti-PBP activity and an in vitro cytotoxicity evaluation were performed. Furosemide decreased the PBP2a levels in MRSA by 21.5% compared to the control. However, the furosemide analogs 3b and 4a demonstrated superior anti-PBP activity (55.9 and 57.1 % reduction in the expression of PBP2a, respectively). In addition, compound 4a was nearly nontoxic to normal WI-38 cells (IC 50  = 248.60 μg /mL) indicating its high safety profile. Finally, the ability of furosemide and compounds 3b and 4a to bind to the target PBP2a enzyme has also been supported by molecular docking research.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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