Rational design of azo-aminopyrimidine derivatives as the potent lepidoptera-exclusive chitinase inhibitors

Abstract

Ostrinia furnacalis (O. furnacalis) is a commonly occurring agricultural pest that can severely impact corn yield and quality. Therefore, establishing and implementing effective control methods against O. furnacalis are of great significance. Chemical insecticides remain the most effective means to mitigate the damage caused by O. furnacalis. With the increasing resistance of O. furnacalis to insecticides, it is imperative to identify and develop compounds with novel mechanisms of action and high safety. The chitinase OfChi-h, identified and characterized in O. furnacalis, has been recognized as a potential insecticide target. In this study, a series of azo-aminopyrimidine analogues were synthesized as OfChi-h inhibitors employing rational molecular optimization. Among them, compounds 9b, 10a and 10g exhibited K_i values of 23.2, 19.4, and 43.2 nM against OfChi-h, respectively. Molecular docking studies were carried out to explore the molecular basis for the high efficacy of these compounds and OfChi-h. In addition, the morphological changes of the cuticle in inhibitor-treated O. furnacalis larvae were assessed using scanning electron microscopy. Furthermore, the target compounds were assayed in leaf dipping and pot experiments, with compound 10a exhibiting greater insecticidal activity against Plutella xylostella (P. xylostella) and O. furnacalis than diflubenzuron and chlorbenzuron. At the same time, the toxicity of these compounds to natural enemies Trichogramma ostriniae and rats was negligible. The present study demonstrates that the azo-aminopyrimidine skeleton can be used as a novel, low-cost scaffold for developing insect chitinolytic enzyme inhibitors, with the potential to be utilized as new environmentally friendly insecticides.