Breaking the toxicity-efficacy tradeoff: Discovery of isoxazoline derivative as candidate for green insecticide.

Commercially available insecticides generally suffer from high toxicity to bees. The inherent toxicity-efficacy trade-off in traditional insecticides has become a major bottleneck constraining the advancement of green pesticide innovation. In this study, a series of novel triazole amide isoxazoline derivatives were designed and synthesized using DP-9 as the lead compound. This study indicates that the "toxicity-efficacy trade-off" bottleneck has been preliminarily overcome. The representative compound T12 displayed significantly improved efficacy against Plutella xylostella (1.4-fold improvement over DP-9) and Spodoptera frugiperda (comparable to DP-9). Remarkably, T12 showed substantially reduced acute oral toxicity to Apis mellifera (LD50 = 11.26 μg/bee), representing a 17-fold greater safety factor than fluxametamide, representing a 54-fold greater safety factor than DP-9, but has a lower safety factor than tetrachlorantraniliprole (LD50 > 15.21 μg/bee). The DFT calculations indicate that electrostatic interactions between the amino/carbonyl regions and the GABA receptor of Plutella xylostella are key factors for bioactivity. Molecular dynamics simulations demonstrate that the triazole and CN groups are the critical moieties contributing to bee toxicity. The compound T12 combines high insecticidal activity with low bee toxicity. This study successfully achieved the targeted introduction of amide bonds into the highly toxic leading compound DP-9 for the first time, effectively reducing bee toxicity while maintaining high insecticidal activity, thereby providing innovative design strategies and candidate molecules for developing environmentally friendly pesticides.