Novel acylpiperidine analogues as potential aphid repellent agents: Rational design, synthesis and repellent activity

Abstract

Odorant-binding protein (OBP) is a promising potential target and can be used as a template for developing insect control agents due to its ability to bind to and transport semiochemicals to olfactory receptors, thus triggering behavioural responses among insects. In this study, 27 novel acylpiperidine analogues were designed and synthesised by introducing the hydrophobic long chain of the aphid alarm pheromone (E)-β-farnesene (EβF) into the polar acylpiperidine group of the commercial insect repellent icaridine based on the binding cavity characteristics of an OBP of the pea aphid Acyrthosiphon pisum, ApisOBP3. Compound 14c displayed good repellent activity against the pea aphids with a repellence rate of 61.5% at a concentration of 6 μg/μL. The equilibrium dissociation constant (Ki) of compound 14c against ApisOBP3 was 20.92 μM in competitive fluorescence binding assays; this value is similar to the Ki of the commercial insect repellent icaridine (20.56 μM). Molecular dynamics simulation revealed that the EβF long chain of compound 14c showed considerable hydrophobic interactions with the binding domain of ApisOBP3. Moreover, the acylpiperidine moiety of compound 14c formed one hydrogen bond and multiple carbon–hydrogen bonds with the Phe2 and Asn109 residues, respectively. The binding free energy analysis indicated that the contribution of the van der Waals force to the binding affinity was approximately twice as great as that of the electrostatic force. These studies provide significant guidance for the rational designing and efficient identification of novel insect repellent agents.