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

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 PxChs1. A series of V-type amidazoles mimicking the catalytic sites of PxChs1 were synthesized. Notably, compounds 6k and 6l exhibited significant insecticidal efficacy against Plutella xylostella, with LC₅₀ 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 PxChs1. Notably, compounds 6k and 6l exhibited minimal toxicity toward Chinese honeybees and Danio rerio. This study provides a valuable approach for developing innovative PxChs1 inhibitors despite a limited structural understanding of the protein.

AlphaFold; azole; chitin synthase; insecticide; molecular docking.