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