Design, Synthesis, and Antifungal Evaluation of Novel Perillaldehyde Oxadiazole Derivatives Bearing Hydrazide/Amide Moiety as Potential Succinate Dehydrogenase Inhibitors

Abstract To discover novel fungicides, four series of oxadiazole-containing perillaldehyde derivatives bearing hydrazide/amide moieties were designed, synthesized and evaluated for antifungal activity against seven phytopathogens. Among them, a perillyl-1,3,4-oxadiazole-hydrazide derivative 6d exhibited the strongest activity against Monilinia fructicola (EC50: 0.10 mg/L), outperforming bixafen and carbendazim, and it displayed a favorable safety profile toward nontarget plants and animals. In vivo assays showed that 6d provided outstanding protective and curative effects on M. fructicola-infected peaches. Mechanism studies revealed that 6d induced morphological and ultrastructural damage, disrupted cell membrane integrity, triggered reactive oxygen species accumulation and loss of mitochondrial membrane potential, as well as inhibited succinate dehydrogenase (SDH) activity. Molecular docking further elucidated its binding mode with SDH. Transcriptomic analysis confirmed that 6d significantly altered gene expression related to oxidoreductase activity, oxidation–reduction processes and transmembrane transporter activity. These results demonstrate that 6d is a promising SDH-targeting fungicide candidate for controlling peach brown rot.