Hybrid Imidazo1,2-apyrimidine Derivatives with Thiophene and Schiff Base Linkages: Synthesis, Characterization, and Bioactivity Profiling

The emergence of multidrug resistance and the urgent need for new therapeutic agents have driven the development of novel heterocyclic scaffolds with broad-spectrum bioactivity. In this study, a series of imidazo1,2-apyrimidine–Schiff base hybrids were synthesized through a multi-step protocol starting from 2-acetylthiophene. The synthesized compounds were structurally characterized using 1H NMR, 13C NMR, FTIR, and mass spectrometry. Biological screening demonstrated that several derivatives exhibited promising antimicrobial, antifungal, antimalarial, and antitubercular activities. Among them, five compounds emerged as the most active candidates, one of them showed potent antifungal and antimalarial efficacy, while another one displayed notable antitubercular activity. Antimalarial assays revealed sub-micromolar IC50 values (0.62–0.70 µg/mL) for the most active compounds, highlighting their strong inhibitory potential against Plasmodium falciparum. To complement the experimental studies, molecular docking was performed against the target protein (PDB ID: 1KZN) using AutoDock Vina. Two compounds with docking scores –8.5 kcal/mol–8.1 kcal/mol showed the highest binding affinities, supported by extensive hydrophobic interactions with key residues (ARG A:76, GLU A:50, THR A:165, ILE A:78). The docking results correlated well with experimental activity, providing mechanistic insight into the potential modes of action. Overall, the integrated biological and computational findings highlight this imidazo1,2-apyrimidine–Schiff base series as promising scaffolds for the development of new antimicrobial, antifungal, antimalarial, and antitubercular agents. These results provide a strong foundation for further structural optimization, ADMET profiling, and in vivo validation of the most active candidates.