Synthesis, Biological Evaluation, Molecular Docking Study and Acute Oral Toxicity Study of Coupled Imidazole-Pyrimidine Derivatives

Background: A novel series of 4-[(4,5-diphenyl-2-substituted phenyl/heteryl)-1H-imidazole- 1-yl]pyrimidine-2(1H)-one derivatives 5 (a-o) were synthesized using Green protocol. Methods: The structures of the synthesized derivatives were established by IR, NMR, Mass spectra and elemental analysis. The synthesized coupled derivatives 5 (a-o) were evaluated for their in vitro antifungal activity against six fungi strains. Compounds 5h, 5i and 5j exhibited the most promising antifungal activity. The mode of action of the most promising antifungal compounds 5i and 5j was established by ergosterol extraction and quantitation assay. From the ergosterol extraction and quantitation assay finding that the compounds 5i and 5j act by the inhibition of ergosterol biosynthesis in C. albicans. Results: The molecular docking study of most active compounds 5i and 5j had shown good binding interactions with the lanosterol 14 α-demethylase. The synthesized compounds were also analyzed for ADMET properties and the result showed that compounds could be exploited as an oral drug candidate. To establish the antifungal selectivity and safety, the most active compounds were further tested for cytotoxicity against human cancer cell lines HeLa and PC-3 and showed no significant cytotoxic activity. The in vivo acute oral toxicity study shows that the synthesized active compounds 5i and 5j were non toxic in nature. Conclusion: All the above studies clearly indicated that novel, selective and specific inhibitors against the lanosterol 14 α-demethylase have been synthesized, which can be used as lead antifungal molecules.