Discovery, Optimization, and Biological Evaluation of Novel (1,2,4-Triazol-1-yl)propan-2-ol Derivatives as Potent Demethylation Inhibitors.
TL;DR
Compound 6o represents a promising lead for novel demethylation inhibitor fungicides for crop protection and exhibited good biosafety toward apple and rice seedlings.
Abstract
Sterol 14α-demethylase (CYP51) and squalene epoxidase (SE) are rate-limiting enzymes in ergosterol biosynthesis, and their inhibition markedly retards fungal growth. A series of novel (1,2,4-triazol-1-yl)propan-2-ol derivatives were designed based on reported CYP51/SE inhibitor scaffolds. Bioassays demonstrated that compound 6o exhibited broad-spectrum antifungal activity, with EC50 values of 0.25, 0.38, and 0.49 mg/L against Valsa mali, Rhizoctonia solani, and Curvularia lunata, respectively. At 100 mg/L, compound 6o achieved 84.6% in vivo control efficacy against V. mali, comparable to difenoconazole (88.1%). Further studies revealed that compound 6o blocked ergosterol synthesis, damaged cell membrane integrity, elevated membrane permeability, and triggered intracellular ROS accumulation in V. mali. Enzyme activity tests, molecular docking, and qRT-PCR analyses suggested that compound 6o acts as a dual inhibitor of CYP51 and SE. Moreover, compound 6o exhibited good biosafety toward apple and rice seedlings. Collectively, compound 6o represents a promising lead for novel demethylation inhibitor fungicides for crop protection.