Discovery of A Safe and Effective Hemipteran Insecticide: α6 nAChR-Targeting Non-Mesoionic Scaffold

Abstract Triflumezopyrim, a mesoionic insecticide targeting nAChRs, effectively controls resistant hemipteran pests like planthoppers but raises concerns over non-target toxicity, especially to honeybees. In this study, we identified compound Q1, a pyrido[2,3-d]pyrimidine-2,4-dione derivative, which exhibits slightly superior insecticidal activity against hemipteran pests compared to triflumezopyrim, with an LC50 value of 2.83 mg/L against Acyrthosiphon pisum, whereas triflumezopyrim shows an LC50 of 2.92 mg/L. Multi-omics integrated analysis confirmed that α6 serves as a key regulatory hub for maintaining normal energy metabolism and redox homeostasis in aphids. Q1 specifically targets the nAChR α6 subunit, disrupting ionic balance, inducing ROS bursts, and inhibiting ATP synthesis, ultimately leading to insect death. Importantly, Q1 exhibited no obvious toxicity to non-target organisms including honeybees, fish, and earthworms at tested concentrations. These findings highlight Q1 as a promising and safer alternative for sustainable hemipteran pest management.