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 8c was the best (LC50 = 54.68 μg/mL) against Myzus persicae, 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 Ls-AChBP. Notably, compound 8c also exhibited low acute contact toxicity to Apis mellifera. An innovative mutated AChBP model simulating bee nAChR was generated first in silico, and the low bee toxicity of compound 8c 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.