Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT4 receptors activities for the treatment of Alzheimer’s disease
Julien Lalut, Hugo Payan, Audrey Davis, Cédric Lecoutey, Rémi Legay, Jana Sopková‐de Oliveira Santos, Sylvie Claeysen, Patrick Dallemagne, Christophe Rochais
Abstract
Abstract A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT 4 R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar K i for 5-HT 4 R.