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

Chi-h, a lepidopteran-exclusive glycoside hydrolase family 18 (GH18) chitinase from the agricultural insect pest , is a promising molecular target candidate for pest control and management. Berberine (), 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 was a moderate inhibitor of Chi-h with a i of 16.1 μM. To improve its efficacy, a series of derivatives featuring an ester bond linked to an aromatic or heterocyclic aromatic ring at the 9-position were designed and evaluated as effective Chi-h inhibitors. The most potent compound, compound with a nicotinate group, exhibited a i of 0.093 μM. Molecular docking analysis suggested that the common binding mode of 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 derivative to 4th-instar larvae in an artificial diet led to their impaired growth and metamorphosis. This work provides a new starting point for the modification of for use in pest control.