AlphaFold-Assisted Design and Synthesis of V-Type Amidazoles as Chitin Synthase Inhibitors against .

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 Chs1. A series of V-type amidazoles mimicking the catalytic sites of Chs1 were synthesized. Notably, compounds and exhibited significant insecticidal efficacy against , with LC 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 Chs1. Notably, compounds and exhibited minimal toxicity toward Chinese honeybees and . This study provides a valuable approach for developing innovative Chs1 inhibitors despite a limited structural understanding of the protein.