Imidazole derivatives as novel and potent antifungal agents: Synthesis, biological evaluation, molecular docking study, molecular dynamic simulation and ADME prediction

Abstract

Fungal infections have become a serious threat to human health due to their high incidence and mortality. In this study, a new set of imidazole derivatives (7a-f) were synthesized and their chemical structures were characterized using spectroscopic techniques including IR, 1H-NMR, 13C-NMR and Mass. In the following, the antifungal activities of these derivatives were evaluated against several yeasts, aspergillus and dermatophyte species using the CLSI method. In addition, to check the safety of the synthesized compounds, the in vitro cytotoxicity activity of these compounds was investigated towards normal human fibroblasts cell line (MRC-5) using MTT assay. The obtained biological results indicated that these compounds acted as the most potential antifungal agents. In particular, compounds 7c, 7d and 7f exhibited excellent activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei, Candida dubliniensis, Candida parapsilosis, and Cryptococcus neoformans species with MIC50 values in the range of 0.5-16 µg/ml. The cytotoxicity results showed that these compounds have low toxicity against normal human fibroblasts cell line (MRC-5). Additionally, molecular modelling studies and molecular dynamic simulation were carried out to predict the binding energy and possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51) as a conventional target for azole derivatives. In silico ADME study was also performed to investigate the physicochemical features of the synthesized imidazole derivatives. According to the results, these compounds can be considered as promising antifungal candidates for further development.