Novel cinnamamide-dibenzylamine hybrids: Potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer's disease

摘要

Abstract By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In?vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β -amyloid (A β ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12?cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Overall, all of these outstanding in?vitro results in combination with promising in?vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation. Graphical abstract Display Omitted Highlights ? Cinnamamide-dibenzylamine hybrids were designed, synthesized and evaluated. ? The new hybrids were obtained by fusing cinnamamide with AP2238. ? Most of the hybrids exhibited a significant ability to inhibit ChEs. ? Some had the ability of anti-Aβ aggregation, antioxidant and biometal chelating. ? 7f is a balance multitargeted candidate worthy of further investigation.