3D-QSAR-Guided Lead Discovery of 4-(3,4,5-Trifluorophenyl)but-3-en-2-amide as Succinate Dehydrogenase Inhibitor

To discover a novel succinate dehydrogenase (SDH) inhibition fungicide, a series of 4-(3,4,5-trifluorophenyl)but-3-en-2-amides were designed by a combination of 3D-QSAR and substructure splicing of fluxapyroxad and pydiflumetofen. In vitro fungicidal bioassays demonstrated that <b>5a</b> exhibited a broad-spectrum of fungicidal activity against <i>Alternaria solani</i>, <i>Cercospora arachidicola</i>, <i>Fusarium graminearum</i>, <i>Fusarium verticillioides</i>, <i>Rhizoctonia solani</i>, and <i>Sclerotinia sclerotiorum</i>, with EC₅₀ values falling between 3.74 and 19.8 μg/mL. Enzymatic activity assays revealed that the inhibition of <b>5a</b> was lower than that of fluxapyroxad, with an IC₅₀ of 12.5 vs 0.04 μg/mL, respectively. Scanning electron microscopy showed that <b>5a</b> was effective in inhibiting fungal hyphae growth. Molecular docking and molecular dynamics (MD) simulations showed that <b>5a</b> exhibited binding patterns similar to those of fluxapyroxad and pydiflumetofen. Binding free energy calculations and decomposition analyses provided insight into the residue interactions of <b>5a</b> during the MD simulation. These findings suggest that <b>5a</b> is a novel fungicidal candidate for further investigation.