Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

Dual-target drug design was considered as the more reasonable antifungal strategy. In this study, three different series of novel compounds were designed using the skeleton screening and splicing method based on dual-target enzyme features, and their structures were synthesized and characterized. Among them, target compounds 5a-1-2, 14b-1-2, and 14c-2-1 with excellent antifungal activity (0.125–2.0 μg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds blocked the ergosterol biosynthesis pathway by inhibiting the core enzyme CYP51, which effectively induced rapid accumulation of reactive oxygen species, damaged the mitochondrial function, and eventually led to the occurrence of fungal apoptosis. On the other hand, these compounds also inhibited the inflammatory inducible enzyme cyclooxygenase-2, which further affected the expression of inflammatory factors and body’s immune function. In conclusion, this study discovered potential target compounds, which could accelerate the rehabilitation process of the infected region.