Design of Novel Furan β-Butenolide Compounds with Low Bee Toxicity Based on the Binding Pharmacophore Model to AChBP

Developing novel-structured nAChR modulators is urgent due to the high bee toxicity of current neonicotinoids. In this work, a pharmacophore model of an nAChR modulator was generated, and a series of novel furan β-butenolide compounds were designed and synthesized. The bioassay study demonstrated that the insecticidal activity of compound <b>8c</b> was the best (LC₅₀ = 54.68 μg/mL) against <i>Myzus persicae</i>, possibly due to its binding mode being more similar to that of flupyradifurone, as well as its interactions with specific key residues (ARG55, TRP143, and TYR89) within <i>Ls</i>-AChBP. Notably, compound <b>8c</b> also exhibited low acute contact toxicity to <i>Apis mellifera</i>. An innovative mutated AChBP model simulating bee nAChR was generated first <i>in silico</i>, and the low bee toxicity of compound <b>8c</b> was attributed to the decrease of its binding energy with the mutated bee-like AChBP. This study presents an innovative approach to design and verify β-butenolide compounds as low-bee-toxicity insecticidal candidates.