Isoxazole-Based Optimization of Pyrido[1,2-]pyrimidine Mesoionic Compounds for Discovering Aphicidal Molecules Tolerated by Honeybees.

For a long time, the poor selectivity of insecticides between pollinating insects and pests has posed challenges to enabling biodiversity. Currently, there have been relatively few successes involving the development of agrochemicals that are safe for bees. We here disclose an achievement in this context: an isoxazole-based modification of pyrido[1,2-]pyrimidine structures is implemented to provide 26 new mesoionics () for aphicidal bioassays. The resulting derivatives and show an outstanding lethal effect on (), with LC values of 1.68 and 1.46 mg/L, respectively, lower in contrast to triflumezopyrim () (LC = 2.66 mg/L). Interestingly, structurally similar compounds and exhibit significant differences in acute oral experiments with , with (LD = 0.87 μg a.i./bee) demonstrating toxicity comparable to that of (LD = 0.72 μg a.i./bee), whereas (LD = 14.65 μg a.i./bee) is found to be slightly level. Comprehensive analyses of proteomics, reverse transcription quantitative polymerase chain reaction (RT-qPCR), enzyme activity assays, and molecular docking results suggest that exerts its insecticidal function by modulating pest nicotinic acetylcholine receptors, specifically subunits β1 and β4. The observed tolerance of bees to may be attributed to their metabolic advantages. This study is expected to contribute valuable insights into developing mesoionic insecticides with better selectivity.