Elsebaei Mohamed M, Ezzat Hany G, Helal Ahmed M, El-Shershaby Mohamed H, Abdulrahman Mohammed S, Alsedawy Moaz, Aljohani Ahmed K B, Almaghrabi Mohammed, Alsulaimany Marwa, Almohaywi Basmah, Alghamdi Read, Miski Samar F, Musa Arafa, Ahmed Hany E A
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University Nasr City 11884 Cairo Egypt
Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University Nasr City 11884 Cairo Egypt.
RSC Adv. 2024 Dec 20;14(54):39977-39994. doi: 10.1039/d4ra07367c. eCollection 2024 Dec 17.
Antimicrobial resistance in methicillin-resistant (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). 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.
耐甲氧西林金黄色葡萄球菌（MRSA）中的抗菌耐药性是一项重大的全球健康挑战。本研究报告了新型苯基三唑衍生物作为潜在抗MRSA药物的设计与合成。新的骨架用1,2,3 - 三唑环取代了噻唑核心，增强了抗菌效力和理化性质。合成并评估了一系列衍生物，其中四种化合物（20、23、29和30）对MRSA表现出显著活性（MIC≤4μg/mL）。化合物29成为最有前景的候选物，在时间杀菌试验中显示出快速杀菌活性且性能优于万古霉素。它对细菌细胞表现出选择性毒性，在人细胞系中细胞毒性极小，溶血活性低。机制研究表明，化合物29通过与青霉素结合蛋白2a（PBP2a）结合靶向细菌细胞壁，破坏细胞壁完整性。此外，它表现出很强的抗生物膜活性，可使MRSA生物膜减少多达40%。初步药代动力学概况显示出良好的概况，包括延长的血浆半衰期和良好的口服生物利用度。这些结果表明，化合物29是对抗MRSA进一步开发的有前景的先导物。
