Hit Identification Against Candida Albicans: Design, Synthesis, Molecular Docking and Biological Evaluation of Hybrid Styryl-Quinoxaline Based Analogues.

Abstract

The occurrence of invasive fungal infections (IFIs) and the incidence of resistant fungal pathogens have increased dramatically, leading to high morbidity and mortality especially with immune-compromised patients. Owing to their multifunctional pharmacological profiles, quinoxalines attract widespread attention being a part of several biologically and technologically relevant compounds. Herein, we report the design, synthesis, structural characterization, and biological screening of a series of new quinoxaline-based scaffolds. The antimicrobial activities of the synthesized compounds were assessed against a panel of bacterial species as well as representative fungi. Interestingly, N-(3-chlorophenyl)-2-(3-(2-hydroxystyryl)quinoxalin-2-yl) hydrazinecarboxamide (3a) displayed significant antifungal activity against Candida albicans (MIC50 ≤0.25 µg/mL) compared to that of the reference drug fluconazole (MIC50 =0.125 µg/mL). Molecular docking studies showed that the potency of our compounds could be attributed to the inhibition of fungal squalene epoxidase enzyme. Additionally, all synthesized compounds were almost neither toxic to human embryonic kidney cells (CC50 >32.0 µg/mL) nor to human red blood cells (HC10 >32.0 µg/mL). The above finding results suggested that compounds 3a is a promising lead compound that merits further optimization and development as antifungal candidate.