Novel Coumarin–Pyridine Hybrids as Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer’s Disease

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 (IC(50) = 2–144 nM) and remarkable butyrylcholinesterase (BuChE) inhibition property (IC(50) = 9–123 nM) compared to donepezil as the standard drug (IC(50) = 14 and 275 nM, respectively). Compound 3f as the best AChE inhibitor (IC(50) = 2 nM) showed acceptable BuChE inhibition activity (IC(50) = 24 nM), 100 times more active than the standard drug. Compound 3f could also significantly protect PC12 and SH-SY5Y cells against H(2)O(2)-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.