Abstract
In this research, a series of coumarin-based scaffolds linked to pyridine derivatives via a flexible aliphatic linkage were synthesized and assessed as multifunctional anti-AD agents. All the compounds showed acceptable acetylcholinesterase (AChE) inhibition activity in the nanomolar range (IC50 = 2-144nM) and remarkable butyrylcholinesterase (BuChE) inhibition property (IC50 = 9-123nM) compared to donepezil as the standard drug (IC50 = 14 and 275nM, respectively). Compound 3f as the best AChE inhibitor (IC50 = 2nM) showed acceptable BuChE inhibition activity (IC50 = 24nM), 100 times more active than the standard drug. Compound 3f could also significantly protect PC12 and SH-SY5Y cells against H2O2-induced cell death and amyloid toxicity, respectively, superior to the standard drugs. It could interestingly reduce β-amyloid self and AChE-induced aggregation, more potent than the standard drug. All the results suggest that compound 3f could be considered as a promising multi-target-directed ligand (MTDL) against AD.
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