Evaluation of quinoxaline derivatives as potential ergosterol biosynthesis inhibitors: design, synthesis, ADMET, molecular docking studies, and antifungal activities

Abstract

Because of the increased infection incidence and the advent of medication resistance, fungi have become a severe medical problem. Ergosterol is a structural component of the fungal cell membrane, and its synthetases (14α-demethylase (CYP51)) are thought to be the key to inhibiting ergosterol synthesis. Based on the active site (CYP51) analysis, we created a series of quinoxaline derivatives in this study. Following that, these target compounds were produced and tested for antifungal efficacy. The majority of the compounds show significant antifungal activity against a variety of Candida species. Compounds 9, 11, 17, 20, and 21 have antifungal properties that are similar to the positive control medicines and have considerable inhibitory effects, with MIC50 values ranging from 0.78 to 3.12 μg/mL. Compound 9 has the strongest antifungal activity against all Candida species, outperforming Ketoconazole and Fluconazole, and was thought to be the series' most active compound. As a result, the action mechanism for the most powerful blows was investigated further. They can alter ergosterol synthesis by blocking the activity of the 14α-demethylase (CYP51) target, according to preliminary mechanisms. According to this study, compounds 9, 11, 17, 20, and 21 have an efficient effect on the ergosterol production pathway. Moreover, the cytotoxicity of the most promising compounds was investigated, revealing the importance of 9, 11, 17, 20, and 21 hits as prospective anticandidal therapeutics. Furthermore, the ADMET characteristics, as well as the created binding models, will be valuable for further lead optimization.