Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC = 0.58 ± 0.05 μM; MAO-B: IC = 0.41 ± 0.04 μM). Further molecular modeling and kinetic investigations revealed that compound was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.