Exploring the N-terminus region: Synthesis, bioactivity and 3D-QSAR of allatostatin analogs as novel insect growth regulators

Abstract

Allatostatins (ASTs), a family of insect neuropeptide, can inhibit juvenile hormone (JH) biosynthesis by the corpora allata (CA) in Diploptera punctata, and therefore be regarded as potential leads for the discovery of new insect growth regulators (IGRs). But several shortcomings, such as their sensitivity to peptidases and high cost, impeded their practical application in pest management. In order to discover new IGRs, one AST analog B1 possessing non-peptide group was discovered with high ability to inhibit JH biosynthesis in vitro (IC50: 0.09μmol/L) in our previous studies. In the present work, two series of B1 analogs with different substituents on the N-terminus region were designed and synthesized. The result suggested that benzene showed better activity than other heterocycles, and the para-substitution on the benzene was beneficial for activity. Moreover, analogs with logP value over 2.0 exhibited good activity, which indicated the hydrophobicity is important to the bioactivity. Three dimension quantitative structure-activity relationship (3D-QSAR) studies were performed to highlight the structural requirements of AST analogs, which demonstrated introduction of bulkier substituents on the N-terminus would increase the activity. Analog II12 (IC50: 0.08μmol/L) exhibited similar inhibitory activity to the lead B1, but its synthetic route was simpler than B1. Therefore, II12 could be used as a new lead compound for the discovery eco-friendly IGRs.