Modified neonicotinoid insecticide with bi-directional selective toxicity and drug resistance

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established based on the molecular structures and the negative logarithm of experimental lethal concentration 50 values (pLC₅₀) of neonicotinoid insecticides. Then, the mechanisms of bi-directional selective toxic effects and drug resistance were determined using homology modeling and molecular docking analyses. The results of the model showed that the 1-, 2-, 4-, and 12- positions of neonicotinoid insecticides strongly affected their toxicity, and that the introduction of bulky or electropositive groups at these positions could increase the pLC₅₀ values. Using Compound 19 as a template, we designed 37 derivatives with greater toxicity (increased by 0.04-11.45%). Among them, 20 derivatives had bioconcentrations lower than that of Compound 19 (reduced by 0.38-147.88%). Further screening of Compound 19 and the 20 derivatives mentioned above by homology modeling and acetylcholine receptors (AChRs) molecular docking analyses showed that 10 derivatives had bi-directional selective toxic effects against pests and bees. Further docking analyses of Compound 19 and these 10 derivatives identified that Derivative-33 showed decreased docking with superoxide dismutase (SOD) and glutathione S transferase (GST) in pests and enhanced docking with these enzymes in bees, indicating bi-directional selective resistance for pests and bees. Accordingly, Derivative-33 was selected as a new insecticide with high toxicity to pests and low toxicity to bees (bi-directional selective toxicity), low resistance in pest populations, and high resistance in bee populations. This study provides valuable reference data and will be useful for the development of strategies to produce new environmentally friendly pesticides.