Design, Synthesis, Bioactive Evaluation, and Molecular Dynamics Simulation of Novel 4 H -Pyrano[3,2- c ]pyridine Analogues as Potential Sterol 14α-Demethylase (CYP51) Inhibitors

To discover potential sterol 14α-demethylase (CYP51) inhibitors, thirty-four unreported 4 -pyrano[3,2- ]pyridine derivatives were designed and synthesized. The assay results indicated that most compounds displayed significant fungicidal activity against , , , , and at 16 μg/mL. The half maximal effective concentration (EC ) values of compounds , , and against were 0.326, 0.530, and 0.610, respectively. Namely, they had better antifungal activity than epoxiconazole (EC = 0.670 μg/mL). Meanwhile, their half maximal inhibitory concentration (IC ) values against CYP51 were 0.377, 0.611, and 0.748 μg/mL, respectively, representing that they also possessed better inhibitory activities than epoxiconazole (IC = 0.802 μg/mL). The fluorescent quenching tests of proteins showed that and had similar quenching patterns to epoxiconazole. The molecular dynamics simulations indicated that the binding free energy of and epoxiconazole to CYP51 was -35.4 and -27.6 kcal/mol, respectively.