Novel Coumarin–Pyridine Hybrids As Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer’S Disease Publisher



Babaei E¹ ; Kucukkilinc TT² ; Jalilibaleh L³ ; Nadri H⁴ ; Oz E² ; Forootanfar H⁵ ; Hosseinzadeh E⁶ ; Akbari T⁷ ; Ardestani MS⁸ ; Firoozpour L³ ; Foroumadi A³ ; Sharifzadeh M⁹ ; Mirjalili BBF¹ ; Khoobi M^{6, 8}
Source: Frontiers in Chemistry Published:2022

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 = 2–144 nM) and remarkable butyrylcholinesterase (BuChE) inhibition property (IC50 = 9–123 nM) compared to donepezil as the standard drug (IC50 = 14 and 275 nM, respectively). Compound 3f as the best AChE inhibitor (IC50 = 2 nM) showed acceptable BuChE inhibition activity (IC50 = 24 nM), 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. Copyright © 2022 Babaei, Kucukkilinc, Jalili-Baleh, Nadri, Oz, Forootanfar, Hosseinzadeh, Akbari, Ardestani, Firoozpour, Foroumadi, Sharifzadeh, Mirjalili and Khoobi.