Design, Synthesis, and Fungicidal Activity Evaluation of 1,2,4-Triazole Fungicides Featuring gem -Difluoromethylthio Moiety

The gem-difluoroalkylthio (−SCF2−) moiety has achieved great success in medicinal chemistry, but its application in agrochemicals remains underexplored because of synthetic challenges. Herein, we report a series of 1,2,4-triazole derivatives bearing the gem-difluoromethylthio group and evaluate their antifungal activities against ten phytopathogenic strains. Compound 7n exhibits potent broad-spectrum activity, with EC50 values of 0.007, 0.121, 0.122, and 0.068 μg/mL against Botrytis cinerea, Phytophthora capsici, Curvularia lunata, and Alternaria solani, respectively, outperforming tebuconazole. In vivo, 7n shows protective and curative efficacy comparable to tebuconazole on apple fruits, tomato fruits, and Suzhou Qing leaves. Mechanistic studies, including scanning electron microscopy (SEM), transcriptomics, qRT-PCR, and molecular docking, indicate that 7n disrupts mycelial morphology, interferes with membrane-associated processes, and inhibits sterol biosynthesis by targeting CYP51. These findings highlight the −SCF2– group as a promising scaffold for novel agricultural fungicides.