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

Abstract

The insect chitinase Of ChtI from the agricultural pest Ostrinia furnacalis (Asian corn borer) is a promising target for green insecticide design. Of 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, Piper nigrum L., was discovered for the first time to have inhibitory activity toward Of ChtI. The compound−enzyme interaction was presumed to take place between the piperine benzo [d][1,3] dioxole skeleton and subsite −1 of the substrate-binding pocket of Of ChtI. Hence, on the basis of the deduced inhibitory mechanism and crystal structure of the substrate-binding cavity of Of ChtI, compounds 5a−f were designed and synthesized by introducing a butenolide scaffold into the lead compound piperine. The enzymatic activity assay indicated that compounds 5a−f (K i = 1.03−2.04 μM) exhibited approximately 40−80-fold higher inhibitory activity than the lead compound piperine (I) (K i = 81.45 μM) toward Of 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 Of ChtI. Moreover, the in vivo activity assay indicated that these compounds also displayed moderate insecticidal activity toward O. furnacalis. This work introduces the natural product piperine as a starting point for the development of novel insecticides targeting Of ChtI.

Rational Design and Identification of Novel Piperine Derivatives as Multichitinase Inhibitors

“…More notably, the insecticidal activity of Compound 5k was even equivalent to the positive control tebufenozide to some extent. Moreover, Compound 5k was detected to exhibit equivalent or even better insecticidal activity against the Asian corn borer at a lower concentration than the excellent single-chitinase inhibitors butenolide derivatives and the dual-chitinase inhibitor anacardic acid reported in previous studies, 21,35 although the inhibitory activity of Compound 5k against each chitinase was not the most prominent. It is obvious that the multichitinase inhibitor indeed demonstrated better insecticidal activity than those dual-or single-chitinase inhibitors, suggesting that it exhibits better advantages in the control of the Asian corn borer.…”

“…The stomach toxicities of all compounds against O. furnacalis were evaluated by the leaf-dip method using reported procedures. , Maize leaves were dipped into a test solution (5% DMSO solution of tested compounds and 0.2% Tween-90 in distilled water) for 5 s. After air-drying, three treated leaves were placed into a petri dish and infested with 20 3rd-instar larvae of O. furnacalis.…”

“…In accordance with the results demonstrated in Table 1 and Figure 2, piperine was identified as a competitive inhibitor against all three chitinases mentioned above, with considerable K i values fluctuating from 43.78∼83.03 μM, and the K i value against Of ChtI was consistent with that reported in our previous study. 35 Consequently, piperine is a promising lead scaffold for being further optimized to develop novel inhibitors against multiple chitinases in O. furnacalis. Rational Design of Novel Piperine Derivatives as Multichitinase Inhibitors.…”

“…28−34 Besides, our previous studies revealed that piperine was a potential inhibitor scaffold against chitinases in O. furnacalis. 35,36 T h i s c o n t e n t i s Hence, in this study, the inhibitory activities of piperine against Of ChtI, Of ChtII, and Of Chi-h were first evaluated, and then the interaction modes between piperine and the three chitinases were clarified by molecular docking. Subsequently, a series of novel piperine derivatives were rationally designed and then synthesized in this study.…”

Design, synthesis, and insecticidal activity evaluation of piperine derivatives

“…Xu and Yang, (2017 ) found that piperine derivatives show stomach toxicity activity against agricultural pests with effects comparable to the commercial botanical pesticide toosendanin (CN107892685A). Han et al (2021 ) designed a series of compounds that combined the benzo[ d ][1,3]dioxole moiety of piperine, which showed effective insecticidal activity against Ostrinia furnacalis .…”