Diamide insecticides have gained popularity due to their high efficacy and low toxicity to nontarget organisms. However, diamide-associated resistance has emerged recently, causing a significant reduction in their potency, thereby hindering sustainable agricultural development. Here, we explored novel diamide insecticide analogs and, using a structure-based approach, rationally designed and synthesized 28 nitrophenyl substituted anthranilic diamides. Most of the compounds showed moderate to good activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compounds Ia and Im showed extraordinarily high activity and their mode of action was verified on isolated neurons. Additionally, Im exhibited over 10-fold greater potency than chlorantraniliprole in a HEK293 cell line stably expressing S. frugiperda ryanodine receptors (SfRyRs) containing the resistance mutations, G4891E and I4734M. The binding modes of Im in the SfRyRs were predicted using in silico molecular docking analysis. Our novel nitrophenyl substituted anthranilic diamide derivatives provide valuable insights for the design of insecticidal RyR-targeting compounds to effectively control both wild type and diamide insecticide-resistant lepidopteran pests.
Keywords: diamide insecticide; mode of action; nitrophenyl; resistance; ryanodine receptor.