3D-QSAR-Guided Molecule Design and Protein–Ligand Interaction Studies for Discovery of Succinate Dehydrogenase Inhibitors

Succinate dehydrogenase (SDH) is an ideal fungicidal target. Here, a three-dimensional quantitative structure-activity relationship (3D-QSAR) was established based on the data of 74 compounds with activity against <i>Rhizoctonia solani</i>. By integrating our previously reported 3D-QSAR findings with the current model, a series of pyrazole-containing compounds were rationally designed and synthesized. Bioassay results demonstrated that <b>B5</b>, with an EC₅₀ of 0.002 μg/mL against <i>R. solani</i>, outperformed fluxapyroxad (0.01 μg/mL). Enzyme activity assays revealed that the IC₅₀ of <b>B5</b> was 0.12 μM, significantly better than that of fluxapyroxad (0.35 μM). The <i>in vivo</i> fungicidal activity of <b>B5</b> was 94.44% at 200 μg/mL, which was comparable to that of fluxapyroxad (88.89%). Transcriptomic analysis indicated that <b>B5</b> affects the tricarboxylic acid cycle, sharing the same mode of action as the traditional succinate dehydrogenase inhibitors. Molecular docking and molecular dynamics simulations revealed that the binding modes of <b>B5</b> were strongly correlated to its potent antifungal activity. Notably, <b>B5</b>, a lead compound without a thiazole substructure, is worthy of further investigation.