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

  • J Agric Food Chem. 2026 Feb 4;74(4):3407-3415. doi: 10.1021/acs.jafc.5c08678.
Yaru Sun  1  2 ,  Kun Li  1  2 ,  Hao Zhang  1  2 ,  Ruihang Fan  1  2 ,  Rui Li  1  2 ,  Hongyi Wan  1  2 ,  Rongzhang Wu  1  2 ,  Zhihong Wang  1  2 ,  Liangfu Tang  1  2 ,  Zhijin Fan  1  2
Affiliations
  • 1. State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
  • 2. Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
PMID: 41558684 DOI: 10.1021/acs.jafc.5c08678
Abstract

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.

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