A Honeybee-Safer Pyrazolyl Pyrido[1,2- a ]pyrimidine Mesoionic Targeting Fall Armyworm nAChR α1/β2 Subunits

Abstract Spodoptera frugiperda is a highly destructive pest with widespread resistance to conventional insecticides. Mesoionic chemicals are promising for insecticide discovery, yet lepidopteran-active examples remain limited and many raise pollinator-safety concerns. Here, we report a series of pyrazole-decorated mesoionic pyrido[1,2-a]pyrimidine derivatives and identify Q4 as a lepidopteran-active insecticide candidate with potent activity against S. frugiperda, although its potency is slightly lower than that of the commercial standard dicloromezotiaz. Q4 exhibits relatively lower acute contact toxicity toward honeybees, with an acute contact LD50 of 9.83 μg a.i./bee compared with 0.747 μg a.i./bee for dicloromezotiaz. ELISA, enzyme activity assays, and electrophysiological recordings reveal that Q4 disrupts neuronal homeostasis and inhibits nAChR-mediated currents. RT-qPCR and RNA interference assays implicate α1- and β2-containing nAChR subunits as key determinants of activity. This work identifies Q4 as a lepidopteran-active, comparatively honeybee-safer mesoionic lead and provides a basis for sustainable pest management.