Chalcogen-based bioisosteric replacement for discovering new pyrido[1,2-a]pyrimidine mesoionics against lepidopteran pests

Lepidopteran pests are a major driver of global maize yield losses and have evolved substantial resistance to many conventional insecticides. Current management practices lack new active ingredients that are both broadly effective and safe for pollinators. Here, we report a new class of pyrido[1,2- a ]pyrimidinone mesoionic derivatives designed via an oxygen-to-sulfur bioisosteric substitution strategy. Laboratory bioassays identified J2 as an optimal analogue with excellent and broad-spectrum insecticidal activity against Spodoptera frugiperda , Chilo suppressalis , Ostrinia furnacalis , and Plutella xylostella , exhibiting efficacy comparable to the commercial standard dicloromezotiaz. Notably, J2 showed low acute honeybee toxicity, with contact and oral LD 50 values of 16.478 and 16.858 μ g a.i./bee, respectively, which were markedly higher than those of triflumezopyrim and dicloromezotiaz. Preliminary mechanistic studies using enzyme activities, ELISA, RT-qPCR, RNAi, and molecular docking suggest that J2 likely binds to the orthosteric site at the interface of the nAChR α 1/ β 2 subunit in fall armyworm, disrupting neuronal homeostasis and leading to insect mortality. This study provides a promising and safe lead for the sustainable management of lepidopteran pests.