A Piperine-Based Scaffold as a Novel Starting Point to Develop Inhibitors against the Potent Molecular Target ChtI.

The insect chitinase ChtI from the agricultural pest (Asian corn borer) is a promising target for green insecticide design. ChtI is a critical chitinolytic enzyme for the cuticular chitin degradation at the stage of molting. In this study, piperine, a natural amide compound isolated from black pepper, L., was discovered for the first time to have inhibitory activity toward ChtI. The compound-enzyme interaction was presumed to take place between the piperine benzo[][1,3] dioxole skeleton and subsite -1 of the substrate-binding pocket of ChtI. Hence, on the basis of the deduced inhibitory mechanism and crystal structure of the substrate-binding cavity of ChtI, compounds - were designed and synthesized by introducing a butenolide scaffold into the lead compound piperine. The enzymatic activity assay indicated that compounds - ( = 1.03-2.04 μM) exhibited approximately 40-80-fold higher inhibitory activity than the lead compound piperine () ( = 81.45 μM) toward ChtI. The inhibitory mechanism of the piperonyl butenolide compounds was elucidated by molecular dynamics, which demonstrated that the introduced butenolide skeleton improved the binding affinity to ChtI. Moreover, the activity assay indicated that these compounds also displayed moderate insecticidal activity toward . This work introduces the natural product piperine as a starting point for the development of novel insecticides targeting ChtI.