Discovery of Substituted N-Arylindole Diamides as Insecticidal Candidates Targeting Ryanodine Receptor.
Natural products are important sources of bioactive fragments. Based on the scaffold-hopping strategy, 40 novel N-arylindole diamide derivatives with excellent insecticidal activity were synthesized by substituting the pyrazole moiety of chlorantraniliprole (CHL) with a natural indole substructure. Bioassay results demonstrated that compound I ai exhibited a slightly higher LC50 value (LC50 = 0.26 mg·L-1) compared to CHL (LC50 = 0.11 mg·L-1) against Mythimna separata. For Plutella xylostella, compounds I an (LC50 = 1.74 × 10-2 mg·L-1) and I ah (LC50 = 2.19 × 10-2 mg·L-1) showed the same level of biological activity as CHL (LC50 = 8.6 × 10-3 mg·L-1). Mechanism validation experiment revealed that compound I ai could activate the insect ryanodine receptor to induce calcium ion release. Molecular docking, density functional theory calculations, and toxicity assays against Danio rerio validated its biosafety profile. These results will provide important guidance for the discovery of indole-containing diamide insecticides.