Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments

Abstract

Hybrid inhibitors of acetyl-and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin-donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase. K E Y W O R D S biological activity, drug design, hydrolases, medicinal chemistry, structure-activity relationship Arch Pharm Chem Life Sci. 2018;351:e1800194.wileyonlinelibrary.com/journal/ardp

Therapeutic Potential of Multifunctional Derivatives of Cholinesterase Inhibitors

“…Łozińska et al [ 124 ] synthesized a novel series of donepezil-melatonin hybrids as selective inhibitors of BChE. The synthesis was based on coupling reaction of alkylamine-substituted N-benzylpiperidine derivatives and with a carbonate analogue of N-acetylserotonin.…”

Synthesis, Pharmacokinetic Characterization and Antioxidant Capacity of Carotenoid Succinates and Their Melatonin Conjugates

“…Due to its participation in cellular signaling melatonin was found to be a treatment possibility in various neurodegenerative diseases such as Parkinson’s and Alzheimer’s [ 15 ]. The pleiotropic effect of melatonin can be further improved by covalent derivatization, as some examples have already demonstrated [ 16 , 17 , 18 , 19 ].…”