Rational Design and Identification of Novel Piperine Derivatives as Multichitinase Inhibitors.

Asian corn borer ( Ostrinia furnacalis ) is one of the most destructive pests in agriculture. Three chitinases Of ChtI, Of ChtII, and Of Chi-h are regarded as potential targets for discovering novel agrochemicals to control O. furnacalis . In this study, piperine ( K i = 43.78∼83.03 μM) was first shown to exhibit inhibitory activities against all three chitinases. Subsequently, 19 novel piperine derivatives were rationally designed based on the conserved aromatic residues of three chitinases and then synthesized. Among them, Compound 5k ( K i = 11.78∼22.82 μM) was identified as the most effective multichitinase inhibitor and indeed displayed higher insecticidal activity against O. furnacalis than dual- or single-chitinase inhibitors. Molecular mechanism studies clarified that Compound 5k interacted with two conserved TRP and TYR of three chitinases in identical modes through hydrogen bonds, hydrophobic, and π-π interactions. Moreover, the microinjection experiment indicated that Compound 5k exhibited substantial sublethal effects against O. furnacalis by regulating its growth and development. This study provides evidence of multichitinase inhibitors to be applied in the control of O. furnacalis .