Microwave-assisted Synthesis and Antimicrobial Evaluation of Triazolopyrimidine-Based Methanone Derivatives Bearing Trifluoromethyl Substituents

Introduction/Objective: The emergence of antimicrobial resistance has highlighted the urgent need for new therapeutic agents. In this study, we aimed to design and synthesize a series of novel triazolopyrimidine-based methanone derivatives bearing trifluoromethyl substituents and to evaluate their antimicrobial potential. Methods: The derivatives (4a–i) were synthesized through a rapid microwave-assisted multicom-ponent reaction involving substituted benzaldehydes, 4,4,4-trifluoro-1-phenylbutane-1,3-dione, and 1H-1,2,4-triazol-5-amine. The β-diketone intermediates (2a–b) were prepared by Claisen conden-sation of acetophenone and ethyl trifluoroacetate in the presence of ethanol–water (1:1) as a green solvent system under microwave irradiation at 140°C for 5–10 minutes. The antimicrobial activities of the synthesized compounds were assessed by determining their MICs against Gram-positive, Gram-negative, and fungal strains. Results: All synthesized compounds were obtained in good yields. Among them, derivatives 4g, 4f, and 4i demonstrated significant antimicrobial activity, with MIC values comparable to or better than standard reference drugs. Structure–activity relationship (SAR) analysis indicated that substitution patterns and the presence of electron-withdrawing trifluoromethyl groups strongly influenced bio-logical activity. Discussion: The study demonstrates that microwave-assisted multicomponent synthesis is an efficient and environmentally friendly approach to generating bioactive heterocycles. The findings fur-ther establish the importance of trifluoromethyl substitution in enhancing antimicrobial efficacy. Conclusion: This work highlights triazolopyrimidine-based methanone derivatives as promising scaffolds for the development of novel antimicrobial agents. The synthesized compounds, particu-larly 4g, 4f, and 4i, warrant further investigation for potential pharmaceutical applications.