Green Acid Mediated Synthesis of Imidazo[1,2-a]Pyrimidine-Thiazole/1,3,4-Thiadiazole Hybrids: Design, Characterization and In-Vitro Biological Evaluation.

This work reports the design and development of two series of imine-linked imidazo[1,2-a]pyrimidine-thiazole/1,3,4-thiadiazole derivatives using a molecular hybridization approach as anti-tubercular agents. A total of thirty-seven new hybrid compounds (B1-B37) were synthesized and characterized. One final molecule, B20, was structurally confirmed by single-crystal x-ray diffraction analysis. All the final compounds (B1-B37) were tested for activity against the Mycobacterium tuberculosis H37Rv strain. Compounds B5, B26, and B30 exhibited significant inhibitory effects, with MICs of 12.5, 12.5, and 6.25 µg/mL, respectively. All novel final compounds also displayed effective antibacterial action against four bacterial strains S. aureus, E. coli, B. subtilis, and P. aeruginosa. Toxicity tests on mouse fibroblast (L929) cell lines revealed that the highly active anti-TB compounds (B5, B26, and B30) were nontoxic. Furthermore, the outcomes of the in silico ADME evaluation, DFT analysis, molecular docking studies (targeting CYP121 and InhA), and dynamic simulation demonstrated the potent compounds' great potential as prospective scaffolds for the development of novel antitubercular drugs.