Novel “Phenyl-Pyrazoline-Oxadiazole” Ternary Substructure Derivatives: Synthesis, Insecticidal Activities, and Structure–Activity Relationship Study
Jiaxu Tao, Bihong Tian, Hong Tu, Renjiang Guo, Xining Ma, Zhaokai Yang, Jian Wu
Abstract
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 ( Plutella xylostella ) and fall armyworm ( Spodoptera frugiperda ). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against P. xylostella and S. frugiperda . Especially, compound A21 showed insecticidal activity against P. xylostella (LC 50 = 1.2 μg/mL) better than commercial insecticide ethiprole (LC 50 = 2.9 μg/mL) but worse than parasiticide fluralaner (LC 50 = 0.5 μg/mL). Similarly, compound A21 exhibited insecticidal activity to S. frugiperda (LC 50 = 13.2 μg/mL) better than commercial insecticide fipronil (LC 50 = 78.8 μg/mL) but worse than fluralaner (LC 50 = 0.7 μg/mL). Compound A21 could serve as a potential lead compound to control P. xylostella and S. frugiperda . 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 A21 . Molecular dynamics simulations showed that the hydrogen bond of A21 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.