Rational design and synthesis of novel phenyltriazole derivatives targeting MRSA cell wall biosynthesis†

IF 3.9 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY RSC Advances Pub Date : 2024-12-20 DOI:10.1039/D4RA07367C
Mohamed M. Elsebaei, Hany G. Ezzat, Ahmed M. Helal, Mohamed H. El-Shershaby, Mohammed S. Abdulrahman, Moaz Alsedawy., Ahmed K. B. Aljohani, Mohammed Almaghrabi, Marwa Alsulaimany, Basmah Almohaywi, Read Alghamdi, Samar F. Miski, Arafa Musa and Hany E. A. Ahmed
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Abstract

Antimicrobial resistance in methicillin-resistant Staphylococcus aureus (MRSA) is a major global health challenge. This study reports the design and synthesis of novel phenyltriazole derivatives as potential anti-MRSA agents. The new scaffold replaces the thiazole core with a 1,2,3-triazole ring, enhancing antimicrobial efficacy and physicochemical properties. A series of derivatives were synthesized and evaluated, with four compounds (20, 23, 29 and 30) showing significant activity against MRSA (MIC ≤ 4 μg mL−1). Compound 29 emerged as the most promising candidate, showing rapid bactericidal activity and superior performance over vancomycin in time-kill assays. It exhibited selective toxicity against bacterial cells, minimal cytotoxicity in human cell lines and low hemolytic activity. Mechanistic studies showed that compound 29 targets the bacterial cell wall by binding to penicillin-binding protein 2a (PBP2a), disrupting cell wall integrity. Additionally, it showed strong anti-biofilm activity and reduced MRSA biofilms by up to 40%. Preliminary pharmacokinetic profiles suggested a favorable profile, including a prolonged plasma half-life and good oral bioavailability. These results suggest that compound 29 is a promising lead for further development in the fight against MRSA.

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RSC Advances
RSC Advances chemical sciences-
CiteScore
7.50
自引率
2.60%
发文量
3116
审稿时长
1.6 months
期刊介绍: An international, peer-reviewed journal covering all of the chemical sciences, including multidisciplinary and emerging areas. RSC Advances is a gold open access journal allowing researchers free access to research articles, and offering an affordable open access publishing option for authors around the world.
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