Discovery of a Class of Novel Succinate Dehydrogenase Inhibitors Containing a Coumarin Structure

Succinate dehydrogenase (SDH) has emerged as a highly promising target in modern agricultural research, playing a crucial role in developing environmentally friendly and efficient fungicides for combating agricultural pathogens. This study presents the discovery of a novel class of SDH inhibitors (<b>I</b>-<b>III</b>) incorporating coumarin segments achieved through an active fragment swapping and linking strategy. Fungicidal activity assays revealed that several compounds within this series demonstrate significant inhibitory effects against the tested fungal strains. Through comprehensive structure-activity relationship studies, compound <i>N</i>-(1-((3-butyl-4-methyl-2-oxo-2H-chromen-7-yl)oxy)propan-2-yl)-3-(difluoromethyl)-<i>N</i>-methoxy-1-methyl-1H-pyrazole-4-carboxamide (<b>IIk</b>) exhibited potent inhibitory activity against various fungal species. Notably, it demonstrated superior efficacy against <i>S. sclerotiorum</i> with an EC₅₀ value of 1.14 μg/mL, outperforming the commercial control agent thifluzamide (EC₅₀ = 4.90 μg/mL). Molecular docking simulations indicated that hydrophobic interactions serve as the primary binding mechanism between the ligand and SDH. Intriguingly, compound <b>IIk</b> displayed dual functionality, not only acting as an effective fungicide but also promoting the growth of wheat seedlings and <i>Arabidopsis thaliana</i>, resulting in increased plant biomass. Preliminary investigations into its growth-promoting mechanism suggest that <b>IIk</b> enhances the nitrate reductase activity, thereby facilitating plant growth.