Synthesis, characterization, molecular dynamic simulation, and biological assessment of cinnamates linked to imidazole/benzimidazole as a CYP51 inhibitor.

A class of 2-(1H-imidazol-1-yl)-1-phenylethyl cinnamates 6a-6j and 2-(1H-benzo[d]imidazol-1-yl)-1-phenylethyl cinnamates 7a-7j were synthesized, and their synthesis was validated using various spectroscopic techniques like IR, NMR, and Mass spectrometry. In addition, the compounds were assessed for in-vitro antibacterial against gram-positive and gram-negative strains and in-vitro antifungal against six different fungal strains. Compounds 6 g, 7 b, 7f, and 7 g exhibited significant activity against all bacterial strains ranging from MIC = 12.5-50 µg/mL, and compounds 6 g, 7 b, and 7 g exhibited considerable activity against all fungal strains ranging from MFC = 125-200 µg/mL. A molecular docking study indicated that compounds 6 g, 7 b, 7 g, and 7j could be lodged in the active pocket and inhibit C. albicans Sterol 14α-demethylase (CYP51) protein via various interactions, and these studies validate the antifungal results. Different parameters from the 100 ns MD simulation study are investigated to evaluate the dynamic stability of protein-ligand complexes. According to the MD simulation study, the proposed compounds effectively kept their molecular interaction and structural integrity within the C. albicans Sterol 14-demethylase. Compounds 6 g, 7 b, and 7 g are promising lead compounds in searching for novel antifungal drug-like molecules. Furthermore, in silico ADME indicates that these compounds possess drug-like physicochemical properties to be orally bioavailable.Communicated by Ramaswamy H. Sarma.