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Synthesis, Biological Evaluation and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids, as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer's Di

Posted November 16th, 2011 by xbarril
TitleSynthesis, Biological Evaluation and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids, as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer's Di
Publication TypeJournal Article
Year of Publication2011
AuthorsBolea, I, Juarez-Jimenez J, de los Rios C, Chioua M, Pouplana R, Luque FJ, Unzeta M, Marco-Contelles J, Samadi A
JournalJournal of medicinal chemistry
Date Published2011/10/24/
AbstractA new family of multi-target molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzyl piperidine moiety of the AChE inhibitor donepezil (1), and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50= 5.2 +/- 1.1 nM) and MAO-B (IC50= 43.1 +/- 7.9 nM), and a moderately potent inhibitor of AChE (IC50= 0.35 +/- 0.01 M) and BuChE (IC50= 0.46 +/- 0.06 M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A aggregation. Overall, the results suggest that the new compounds are promising multi-target drug candidates with potential impact for Alzheimer's disease therapy.