Efficient selective targeting of CYP51 by oxadiazole derivatives designed from plant cuminaldehyde.

infection represents a global threat with associated high resistance and mortality rate. Azoles such as the triazole drug fluconazole are the frontline therapy against invasive fungal infections; however, the emerging multidrug-resistant strains limit their use. Therefore, a series of novel azole 1-15 derivatives were developed based on a modified natural scaffold to combat the evolved resistance mechanism and to provide improved safety and target selectivity. The antifungal screening against and showed that 10 and 12-14 compounds were the most potent derivatives. Among them, 13 exhibited superior potent activity with MIC values of 0.5 and 0.8 μg mL against and compared to 25 and 600 μg mL for fluconazole, respectively. 13 displayed significant CaCYP51 enzyme inhibition activity in a concentration-dependent manner with an IC 10-fold that of fluconazole, while exhibiting no activity against human CYP50 enzyme or toxicity to human cells. Furthermore, 13 caused a significant reduction of ergosterol content by 70.3% compared to a 35.6% reduction by fluconazole. Homology modeling, molecular docking, and molecular dynamics simulations of CYP51 enzyme indicated the stability and superiority of 13. ADME prediction indicated that 13 fulfils the drug-likeness criteria with good physicochemical properties.