Design, Synthesis, and Antifungal Activity Evaluation of Novel Hydrazide-Containing -Perillaldehyde Derivatives as Potential Fungicides.

In this study, 36 novel hydrazide-containing -perillaldehyde derivatives were designed, synthesized, and evaluated for their antifungal activity. In the antifungal assays, most of the target compounds exhibited remarkable antifungal activity. Notably, compound displayed exceptional antifungal activities against (EC = 0.260 μg/mL), (EC = 0.480 μg/mL), (EC = 0.240 μg/mL), and (EC = 0.512 μg/mL), outperforming carbendazim, which showed EC values of 0.651, 0.804, 0.520, and 0.898 μg/mL, respectively. Meanwhile, assays against and revealed compound 's potential as a novel agricultural antifungal agent. In the investigation of the antifungal mechanism, scanning electron microscopy and transmission electron microscopy observations revealed that compound induced significant morphological alterations in mycelia, including mitochondrial swelling and rupture, thereby inhibiting mycelial growth. Determination of cellular content leakage and propidium iodide (PI) staining experiments indicated that compound compromised the integrity of the cell membrane, leading to cytoplasmic efflux and, subsequently, inhibiting normal mycelial development. The detection of reactive oxygen species indicated that the antifungal activity of compound may stem from inducing accumulation of reactive oxygen species within cells. The mitochondrial membrane potential detection demonstrated that compound could decrease the mitochondrial membrane potential, thereby damaging mitochondria. Furthermore, compound (IC = 14.5 μg/mL) exhibited potent succinate dehydrogenase (SDH) inhibitory activity comparable to that of boscalid (IC = 12.6 μg/mL). Molecular dynamics simulations confirmed that compound could establish strong interactions with key residues of SDH. These results offer significant insights and guidance for the development of novel antifungal agents.