Novel “Phenyl-Pyrazoline-Oxadiazole”\nTernary Substructure Derivatives: Synthesis, Insecticidal Activities,\nand Structure–Activity Relationship Study

In recent years, isoxazole insecticides or parasiticides\ntargeting\nthe γ-aminobutyric acid receptor, such as fluralaner or fluxametamide,\nfeatured a novel chemical structure and exhibited potent insecticidal\nactivity with no-cross resistance. Thus, many research institutes\nhave tried to modify the structures of these agents to find a new\ninsecticide. Previously, the majority of researchers stuck to the\n“phenyl-isoxazole-phenyl” structure, making modifications\nonly to other components. In this study, the “phenyl-isoxazole-phenyl”\nternary motif was modified for the first time based on bioisosterism\ntheory. A series of new derivatives carrying pyrazoline and 1,3,4-oxadiazole\nmoieties were designed and synthesized to investigate their insecticidal\nactivities against the diamondback moth (Plutella xylostella) and fall armyworm (Spodoptera frugiperda). Preliminary bioassay data showed that some of the target compounds\nexhibited good insecticidal activities against P. xylostella and S. frugiperda. Especially, compound <b>A21</b> showed insecticidal activity against P.\nxylostella (LC<sub>50</sub> = 1.2 μg/mL) better\nthan commercial insecticide ethiprole (LC<sub>50</sub> = 2.9 μg/mL)\nbut worse than parasiticide fluralaner (LC<sub>50</sub> = 0.5 μg/mL).\nSimilarly, compound <b>A21</b> exhibited insecticidal activity\nto S. frugiperda (LC<sub>50</sub> =\n13.2 μg/mL) better than commercial insecticide fipronil (LC<sub>50</sub> = 78.8 μg/mL) but worse than fluralaner (LC<sub>50</sub> = 0.7 μg/mL). Compound <b>A21</b> could serve as a potential\nlead compound to control P. xylostella and S. frugiperda. The three-dimensional\nquantitative structure–activity relationship model revealed\nthat the further introduction of an electron-donating group in the\n2- 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\nstudy has identified a new substructure called “phenyl-pyrroline-oxadiazole”\ninstead of the previously known “phenyl-isoxazole-phenyl”\nsubstructure, offering a useful guide for the design of novel insecticide\nmolecules.