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 5a exhibited a broad-spectrum of fungicidal activity against Alternaria solani, Cercospora arachidicola, Fusarium graminearum, Fusarium verticillioides, Rhizoctonia solani, and Sclerotinia sclerotiorum, with EC₅₀ values falling between 3.74 and 19.8 μg/mL. Enzymatic activity assays revealed that the inhibition of 5a was lower than that of fluxapyroxad, with an IC₅₀ of 12.5 vs 0.04 μg/mL, respectively. Scanning electron microscopy showed that 5a was effective in inhibiting Fungal hyphae growth. Molecular docking and molecular dynamics (MD) simulations showed that 5a exhibited binding patterns similar to those of fluxapyroxad and pydiflumetofen. Binding free energy calculations and decomposition analyses provided insight into the residue interactions of 5a during the MD simulation. These findings suggest that 5a is a novel fungicidal candidate for further investigation.

3D-QSAR; fungicidal activity; molecular design; succinate dehydrogenase inhibitor; trifluorophenylbutenamide.