Discovery of α-Methylene-γ-Butyrolactone Derivatives with Hydrazide Moieties as Novel Fungicidal Agents

To discover novel fungicides with unique structures, a series of α-methylene-γ-butyrolactone derivatives were designed and synthesized by incorporating a flexible amide or hydrazide chain through active substructure splicing and linker modification strategies. Bioassay assessments demonstrated that certain hydrazide-containing compounds have potent fungicidal efficacy. Notably, compound 7IIj exhibited broad-spectrum antifungal activity, with EC50 values as low as 0.179, 0.301, 0.647, 0.549, and 0.789 mg/L against Rhizoctonia solani, Physalospora piricola, Botrytis cinerea, Gaeumanomyces graminis, and Valsa mali, respectively. In vivo experiments confirmed the effective fungicidal activity of compound 7IIj, showing an inhibitory rate of 69.7% against V. mali on apple twigs at 200 mg/L. Additionally, at a concentration of 100 mg/L, compound 7IIj demonstrated significant protective and curative effects against R. solani on rice plants. Research on the mechanism of action revealed that compound 7IIj could disrupt hyphal morphology, induce reactive oxygen species (ROS) accumulation, affect mitochondrial membrane potential (MMP), and interfere with respiratory metabolism by binding to complex II. Molecular docking analysis showed significant interactions of compound 7IIj with TRP 173, TYR 58, and ARG 43 in the succinate dehydrogenase (SDH) binding site, resembling the binding mode of fluxapyroxad. These findings suggest that compound 7IIj holds potential as an SDH inhibitor for agricultural disease control.