Design and synthesis of new 2-aminopyrimidine-thiazolidinone hybrids with enhanced antimicrobial activity: in-vitro evaluation and multiscale computational studies.

Abstract

A series of novel 2-aminopyrimidine-thiazolidinone hybrids were designed, synthesized, and evaluated for antimicrobial activity against selected bacterial and fungal pathogens. Structural characterization was accomplished using FT-IR, NMR, and mass spectrometry. Among the synthesized compounds, SPRB21 exhibited the most potent antibacterial activity, with MIC values of 125 μg/mL against Escherichia coli ATCC 25922 and ATCC 11775 and 250 μg/mL against Pseudomonas aeruginosa ATCC BAA-427. SPRB17 also demonstrated promising activity, with MIC values of 250, 250, and 500 μg/mL, respectively, showing activity comparable to vancomycin against E. coli and superior activity against P. aeruginosa. In antifungal studies, SPRB27 displayed the highest activity against Candida albicans ((MICf = 12.15 μg/mL; MFC = 61.42 μg/mL),), while SPRB23 exhibited the best fungicidal activity against Aspergillus niger (MICf = 53.75 μg/mL; MFC = 206.5 μg/mL). Although these compounds were less potent than the standard antifungal drug, fluconazole, they demonstrated notable antifungal efficacy within the synthesized series. Molecular docking against dihydrofolate reductase (DHFR) revealed strong binding affinities for SPRB22 and SPRB23, while SAR studies indicated that electron-withdrawing substituents enhanced antimicrobial potency. SwissADME predictions confirmed favorable drug-likeness and oral bioavailability, and 300 ns molecular dynamics simulations validated the stable binding of SPRB21 and SPRB23 within bacterial and fungal DHFR active sites, respectively. These findings identify the 2-aminopyrimidine-thiazolidinone scaffold as a promising platform for the development of novel antimicrobial agents.