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 (<i>Plutella xylostella</i>) and fall armyworm (<i>Spodoptera frugiperda</i>). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against <i>P. xylostella</i> and <i>S. frugiperda</i>. Especially, compound <b>A21</b> showed insecticidal activity against <i>P. xylostella</i> (LC₅₀ = 1.2 μg/mL) better than commercial insecticide ethiprole (LC₅₀ = 2.9 μg/mL) but worse than parasiticide fluralaner (LC₅₀ = 0.5 μg/mL). Similarly, compound <b>A21</b> exhibited insecticidal activity to <i>S. frugiperda</i> (LC₅₀ = 13.2 μg/mL) better than commercial insecticide fipronil (LC₅₀ = 78.8 μg/mL) but worse than fluralaner (LC₅₀ = 0.7 μg/mL). Compound <b>A21</b> could serve as a potential lead compound to control <i>P. xylostella</i> and <i>S. frugiperda</i>. 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 <b>A21</b>. Molecular dynamics simulations showed that the hydrogen bond of <b>A21</b> 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.