3D-QSAR-Based Molecular Design to Discover Ultrahigh Active N -Phenylpyrazoles as Insecticide Candidates.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal -phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against , , and . Compounds and showed similar activity against as chlorantraniliprole (LC values: 0.21, 0.25, and 0.16 μg mL respectively). Compounds exhibited a 3-fold higher potency against than chlorantraniliprole. For , the potency of and was 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. can dock well with mutated RyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound was found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.