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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., Competing Interests: The authors declare that they have no competing interests. No financial support was received for this work. All authors have contributed significantly to the conception, design, execution, analysis, and interpretation of the work. All authors have reviewed and approved the final manuscript., (This journal is © The Royal Society of Chemistry.)