Discovery of Sennidin B as a Potent Multitarget Inhibitor of Insect Chitinolytic Enzymes

Natural products with multitarget inhibitory activity against insect chitinolytic enzymes offer the potential for developing environmentally friendly insecticides. However, most inhibitors show limited efficacy, hindering their practical application. In this study, inspired by the dimeric structure of phlegmacin B₁, sennidin B, a rhein analogue, was identified as an effective inhibitor of insect chitinolytic enzymes. Sennidin B exhibited a nanomolar <i>K</i>_i value (80 nM) against <i>Of</i>Chi-h from <i>Ostrinia furnacalis</i>, showing at least a 600-fold improvement in potency compared to rhein. Molecular dynamics simulations revealed that sennidin B adopts a folded conformation within the enzyme's active site, enhancing binding affinity through π-π stacking interactions with a key tryptophan residue. Insecticidal assays demonstrated 100% mortality at 5 mM and suppression of larval development at 1 mM. This study positions sennidin B as a lead compound for the development of insecticides targeting the molting process and provides a strategy for the discovery of multitarget inhibitors.