AlphaFold-Assisted Design and Synthesis of V-Type Amidazoles as Chitin Synthase Inhibitors against <i>Plutella xylostella</i>
Haoran Yan, Yuekun Huang, Caixin Yang, Xufeng Zheng, Bo Yang, Yulong Jin, Huipeng Pan, Chaoqun Zhang, Hanhong Xu, Ri‐Yuan Tang
Abstract
Chitin synthase serves as a promising target for developing eco-friendly insecticides. Nevertheless, the lack of structural insights into insect chitin synthase has impeded the rational design of specific inhibitors. Herein, we utilized AlphaFold to predict the structure of Px Chs1. A series of V-type amidazoles mimicking the catalytic sites of Px Chs1 were synthesized. Notably, compounds 6k and 6l exhibited significant insecticidal efficacy against Plutella xylostella, with LC 50 values of 0.789 and 0.951 μg/mL, respectively, and induced profound molting disruptions in the larvae. Moreover, the expression of genes involved in chitin metabolism was significantly downregulated. V-type amidazoles with potent insecticidal activity showed favorable docking interactions with Px Chs1. Notably, compounds 6k and 6l exhibited minimal toxicity toward Chinese honeybees and Danio rerio . This study provides a valuable approach for developing innovative Px Chs1 inhibitors despite a limited structural understanding of the protein.