Novel "Phenyl-Pyrazoline-Oxadiazole" Ternary Substructure Derivatives: Synthesis, Insecticidal Activities, and Structure-Activity Relationship Study.

In recent years, isoxazole insecticides or parasiticides targeting the γ-aminobutyric acid receptor, such as fluralaner or fluxametamide, featured a novel chemical structure and exhibited potent insecticidal activity with no-cross resistance. Thus, many research institutes have tried to modify the structures of these agents to find a new insecticide. Previously, the majority of researchers stuck to the "phenyl-isoxazole-phenyl" structure, making modifications only to other components. In this study, the "phenyl-isoxazole-phenyl" ternary motif was modified for the first time based on bioisosterism theory. A series of new derivatives carrying pyrazoline and 1,3,4-oxadiazole moieties were designed and synthesized to investigate their insecticidal activities against the diamondback moth () and fall armyworm (). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against and . Especially, compound showed insecticidal activity against (LC = 1.2 μg/mL) better than commercial insecticide ethiprole (LC = 2.9 μg/mL) but worse than parasiticide fluralaner (LC = 0.5 μg/mL). Similarly, compound exhibited insecticidal activity to (LC = 13.2 μg/mL) better than commercial insecticide fipronil (LC = 78.8 μg/mL) but worse than fluralaner (LC = 0.7 μg/mL). Compound could serve as a potential lead compound to control and . The three-dimensional quantitative structure-activity relationship model revealed that the further introduction of an electron-donating group in the 2- or 3-site may increase the insecticidal activity of . Molecular dynamics simulations showed that the hydrogen bond of and receptor was important for the binding receptor. This study has identified a new substructure called "phenyl-pyrroline-oxadiazole" instead of the previously known "phenyl-isoxazole-phenyl" substructure, offering a useful guide for the design of novel insecticide molecules.