Structure-Based Virtual Screening of Natural Products and Optimization for the Design and Synthesis of Novel Ce Cht1 Inhibitors as Nematicide Candidates.

Nematode chitinases are critical components of the nematode life cycle, and Ce Cht1 is a potential target for developing novel nematicides. Herein, lunidonine, a natural quinoline alkaloid, was first discovered to have inhibitory activity against Ce Cht1, which was acquired from a library of over 16,000 natural products using a structure-based virtual screening methodology. A pocket-based lead optimization strategy was employed based on the predicted binding mode of lunidonine. Subsequently, a series of benzo[ d ][1,3]dioxole-5-carboxylate derivatives were designed and synthesized, and their inhibitory activities against Ce Cht1 as well as in vitro nematicidal activities against Caenorhabditis elegans were assessed. The analysis of structure-activity relationship and inhibitory mechanisms provided insights into their interactions with the Ce Cht1 active site, which could facilitate future research in improving the potency of the inhibitory activity. Especially, compound a12 interacted well with Ce Cht1 and exhibited excellent in vitro nematicidal activity against C. elegans with a LC 50 value of 41.54 mg/L, suggesting that it could be a promising candidate for a novel chemical nematicide targeting Ce Cht1. The known binding modes and structural features of these inhibitors will contribute to the design of stronger Ce Cht1-based nematicides to control nematodes in agriculture.