Novel Coumarin–Pyridine Hybrids as Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer’s Disease
Elaheh Babaei, Tuba Tüylü Küçükkılınç, Leili Jalili‐Baleh, Hamid Nadri, Esin Öz, Hamid Forootanfar, Elaheh Hosseinzadeh, Tayebeh Akbari, Mehdi Shafiee Ardestani, Loghman Firoozpour, Alireza Foroumadi, Mohammad Sharifzadeh, Bi Bi Fatemeh Mirjalili, Mehdi Khoobi
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 (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.