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

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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.