Scaffold Hopping Combined with 3D-QSAR for the Discovery of Succinate Dehydrogenase Inhibitors Containing...

The utilization of scaffold hopping and computer-aided pesticide design has been demonstrated to be an effective strategy for the discovery of novel succinate dehydrogenase inhibitor (SDHI) fungicides, thereby providing valuable insights into the design of more potent SDHI fungicides. Here, a series of novel N-benzyloxyformamide-containing compounds were designed and synthesized using fluxapyroxad, pydiflumetofen, and tolfenpyrad as leads. These new compounds represent significant innovation in conjunction with 3D-QSAR and scaffold hopping. In vitro fungicidal bioassays indicate that compounds 4c, 4g, 4i, 4m, 4p, 4r, 4s, and 4t show effective activity against Botrytis cinerea with EC₅₀ values ranging from 5.17 to 25.7 μg/mL. Compound 4l also exhibits good inhibitory activity against Alternaria solani with an EC₅₀ value of 7.45 μg/mL. A comprehensive investigation of the fungicidal activity of 4i was conducted by using scanning electron microscopy, enzymatic activity assays, molecular docking, molecular simulations, binding free energy calculations, and decomposition analysis. These results indicate that compound 4i possesses significant potency as a fungicide candidate against B. cinerea.