1 research outputs found
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 C10 possessed excellent dual AChE/MAO-B inhibition both in
terms of potency and equilibrium (AChE: IC50 = 0.58 ±
0.05 μM; MAO-B: IC50 = 0.41 ± 0.04 μM).
Further molecular modeling and kinetic investigations revealed that
compound C10 was a dual-binding inhibitor bound to both
the catalytic anionic site and peripheral anionic site of AChE. In
addition, compound C10 exhibited low neurotoxicity and
potently inhibited AChE enzymatic activity. Furthermore, compound C10 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 C10 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 C10 suggest that it deserves further investigation
as a promising lead for the prospective treatment of AD