Discovery of Novel Low Bee‐Toxicity Aphicidal <i>α</i> ‐Butenolide: Design and Optimization Based on a Progressive Strategy of Acetylcholine Binding Protein and Calculated Oil–Water Partition Coefficient

The development of novel insecticides with low bee toxicity has become increasingly urgent as many high bee-toxicity neonicotinoids have been progressively restricted. In this study, novel halogenated phenyl-substituted α-butenolide compounds were designed, optimized and synthesized through a progressive strategy based on insect nicotinic acetylcholine receptor and the calculated oil-water partition coefficient (ClogP) of compounds. Among these, the difluorophenyl-substituted compound 3cj (lethal medium concentration [LC₅₀] = 40.96 µg/mL) exhibited the highest insecticidal activity against Myzus persicae and a relatively low ClogP of 4.25. The molecular docking study revealed that compound 3cj mainly interacted with two key residues TRP147 and TYR188 of Aplysia californica-acetylcholine-binding protein. The bee-toxicity bioassay and molecular mechanism study indicated that compound 3cj exhibited low acute contact toxicity against Apis mellifera, probably due to its reduced binding energy with the honeybee chimeric receptor AmeIα8/ratβ2. This study provides rational guidance for novel α-butenolide compounds as low bee-toxicity insecticidal candidates based on their target receptors and molecular physicochemical properties.