3D-QSAR Directed Discovery of Novel Halogenated Phenyl 3-Trifluoroethoxypyrazole Containing Ultrahigh Active Insecticidal Anthranilic Diamides.

Pests are one of the major factors causing crop damage and food security problems worldwide. Based on our previous studies on the discovery of insecticidal leads targeting the ryanodine receptors (RyRs), a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to design and synthesize a series of anthranilic diamides containing a halogenated phenyl 3-trifluoroethoxypyrazole moiety. The preliminary bioassays disclosed that IIb , IIIb , and IIIf against Mythimna separata showed comparable activity to chloranthraniliprole (LC 50 : 0.16, 0.16, 0.14, and 0.13 mg·L -1 , respectively). More than half of the target compounds displayed good activity against Plutella xylostella, where IIIf was the most active compound, 25 times more active than chloranthraniliprole (LC 50 : 6.0 × 10 -6 versus 1.5 × 10 -4 mg·L -1 ). For Spodoptera frugiperda , IIIf displayed slightly inferior potency to chlorantraniliprole (LC 50 : 0.47 versus 0.31 mg·L -1 ). For RyR mutants of S. frugiperda (G4891E, I4734M), compound IIIf could show higher affinity than chlorantraniliprole according to the binding mode and energy in molecular docking experiments. Calcium imaging technique, molecular docking, density functional theory calculations, and electrostatic potential studies validated that the RyR was the target of the most active candidate IIIf , which deserves further development.