Novel Inhibitors of an Insect Pest Chitinase: Design and Optimization of 9-O-Aromatic and Heterocyclic Esters of Berberine

Abstract

<i>Of</i>Chi-h, a lepidopteran-exclusive glycoside hydrolase family 18 (GH18) chitinase from the agricultural insect pest <i>Ostrinia furnacalis</i>, is a promising molecular target candidate for pest control and management. Berberine (<b>BER</b>), a traditional Chinese medicine, binds to a wide variety of glycosyl hydrolases via an identical mechanism, showing potential as a pesticide lead compound. In this work, we found that <b>BER</b> was a moderate inhibitor of <i>Of</i>Chi-h with a <i>K</i>i of 16.1 μM. To improve its efficacy, a series of <b>BER</b> derivatives featuring an ester bond linked to an aromatic or heterocyclic aromatic ring at the 9-position were designed and evaluated as effective <i>Of</i>Chi-h inhibitors. The most potent compound, compound <b>19e</b> with a nicotinate group, exhibited a <i>K</i>i of 0.093 μM. Molecular docking analysis suggested that the common binding mode of <b>BER</b> derivatives featured a network of π-π stacking and electrostatic interactions and that the group at the 9-position enhanced the van der Waals and hydrogen bonding interactions. Administration of the <b>BER</b> derivative <b>19c</b> to 4th-instar <i>O. furnacalis</i> larvae in an artificial diet led to their impaired growth and metamorphosis. This work provides a new starting point for the modification of <b>BER</b> for use in pest control.