Identification of novel antifungal agents: antimicrobial evaluation, SAR, ADME-Tox and molecular docking studies of a series of imidazole derivatives

Abstract

Thirty-four imidazole-based compounds synthesized by one-pot catalytic method were evaluated for their antifungal and antibacterial activities against several fungal and bacterial strains. None of the compounds had antibacterial activity. Interestingly, compounds 1, 2, 3, 10 and 15 displayed a strong antifungal activity against all the tested fungal species, while compounds 5, 7, 9, 11, 21 and 27 showed a moderate antifungal activity. To better understand the biological activity of the most active compounds ADME-Tox and molecular docking studies were carried out. Interestingly, compounds 1, 2, 3, 7, 10 and 15 showed excellent bioavailability. In addition, compounds 1, 2 and 3, exhibited good toxicity profiles. Docking studies of the two most active compounds 2 (IC₅₀ of 95 ± 7.07 μM) and 10 (IC₅₀ of 235 ± 7.07 μM) suggested that they might act by inhibiting the fungal lanosterol 14α-demethylase. Therefore, these novel antifungal agents merit further characterization for the development of new antifungal therapeutics.

Keywords: ADME–Tox; Antibacterial; Antifungal; Docking; Imidazole; Structure–activity relationship.

Fig. 1

Synthetic route and structure of the molecules studied in this paper

Fig. 2

Antifungal activity of the studied compounds against Saccharomyces cerevisiae, Candida albicans and Candida krusei. Cells were cultured in the presence of 500 µM of each compound for 24 h and growth rate was then assayed by the OD₆₀₀. Growth in the presence of compound was expressed as a percentage relative to the untreated control. All experiments were carried out in triplicate and means were calculated ± SD. *p < 0.05 versus untreated control

Fig. 3

Binding mode of compounds 2 (a) and 10 (b) with target enzyme CYP51 from S. cerevisiae