Design and structure optimization of novel butenolide derivatives as low bee-toxicity candidates

Abstract

The discovery of new neonicotinoid alternatives with high efficiency against pests and eco-safety toward bees has become an increasingly urgent need in recent years. The relationship between the oil-water partition coefficient (logP) and the bee-toxicity of commercial nicotinic acetylcholine receptor (nAChR) competitive modulators was explored in this work. Compared compounds with a high bee-toxicity, compounds with low bee-toxicity were found to have higher logP values. Therefore, two series of novel butenolide derivatives with different hydrophobic groups were designed and synthesized by including different hydrophobic groups. The insecticidal activity study showed that compounds I-01 (LC50=112.96 μg/mL), II-05 (LC50=124.68 μg/mL), and II-11 (LC50=87.89 μg/mL) were with higher insecticidal activity against Aphis glycines and lower calculated logP values among all synthesized compounds. Molecular dynamics simulations indicated that three butenolide compounds formed some hydrogen bonding or π-π stacking interactions with insect acetylcholine binding protein (AChBP). In addition, the bee-toxicity bioassay also showed that compounds I-01, II-05 and II-11 were with much lower contact bee-toxicity than imidacloprid. The possible mechanism of the bee toxicity of the novel butenolide compounds was explored based on the nAChR function subunit AmeIα8/ratβ2. This study will provide rational guidance on novel butenolide compounds as low-bee-toxicity candidates based on their molecular hydrophobic properties.