3‐Aryl Coumarin Derivatives Bearing Aminoalkoxy Moiety as Multi‐Target‐Directed Ligands against Alzheimer's Disease

Abstract

Two series of novel coumarin derivatives, substituted at 3 and 7 positions with aminoalkoxy groups, are synthesized, characterized, and screened. The effect of amine substituents and the length of cross‐linker are investigated in acetyl‐ and butyrylcholinesterase (AChE and BuChE) inhibition. Target compounds show moderate to potent inhibitory activities against AChE and BuChE. 3‐(3,4‐Dichlorophenyl)‐7‐[4‐(diethylamino)butoxy]‐2H‐chromen‐2‐one (4y) is identified as the most potent compound against AChE (IC50=0.27 μm). Kinetic and molecular modeling studies affirmed that compound 4y works in a mixed‐type way and interacts simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, compound 4y blocks β‐amyloid (Aβ) self‐aggregation with a ratio of 44.11 % at 100 μm and significantly protects PC12 cells from H2O2‐damage in a dose‐dependent manner.

Coumarins as Tool Compounds to Aid the Discovery of Selective Function Modulators of Steroid Hormone Binding Proteins

“…3-phenylcoumarins are utilized widely in the biomedical and pharmaceutical industry. 3-phenylcoumarins bearing aminoalkoxy moiety has been designed to treat Alzheimer’s disease by inhibiting acetylcholinesterase and butyrylcholinesterase [ 51 ]. 3-phenylcoumarins with dihydroxyl substituents in the coumarin core have been studied for antioxidative effect [ 52 , 53 ].…”

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer’s Disease

“…Soybean lipoxygenase inhibition assay was conducted according to a previously published report ( Abdshahzadeh et al, 2019 ). A solution of the target compound was prepared in DMSO, and it was diluted with phosphate buffer (0.1 M, pH = 8.0).…”

“…These hybrids have shown great effect on the central nervous system and attracted great interest in neurodegenerative disorder studies ( Jalili–Baleh et al, 2018c ; Seong et al, 2019 ; Tripathi and Ayyannan, 2019 ). Till now, several research groups have developed multifunctional ligands having interesting results as MTDLs against AD based on coumarin derivatives bearing an N -benzyl moiety ( Rahmani–Nezhad et al, 2015 ; Piazzi et al, 2008 ; Abdshahzadeh et al, 2019 ; Kumari et al, 2017 ; Saeedi et al, 2017 ; Jalili–Baleh et al, 2018b ) or cross-linked to appropriate pharmacophores via 1,2,3-triazoles ( Figure 1 ) ( Bozorov et al, 2019 ; Arafa and Nayl, 2019 ; Lipeeva, et al, 2019 ; Asgari et al, 2019 ; Xu, et al, 2019 ).…”

3-Phenylcoumarins as a Privileged Scaffold in Medicinal Chemistry: The Landmarks of the Past Decade

“…Kinetic and molecular modelling studies proved that compound 7 works in a mixed-type approach, and interacts concomitantly with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 7 blocks β-amyloid (Aβ) self-aggregation with a ratio of 44% at 100 µM, and significantly protects rat pheochromocytoma (PC12) cells from hydrogen peroxide (H 2 O 2 )damage in a dose-dependent way [78]. The 7-substitution of 3-phenylcoumarins has also been used as a building block for a novel series of coumarin-lipoic acid conjugates, resulting in compound 8, the most potent AChE inhibitor, showing a good inhibitory effect on Aβaggregation and intracellular ROS formation, as well as the ability of selective bio-metal chelation and neuroprotection against H 2 O 2 -and Aβ1-42-induced cytotoxicity [79,80].…”