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 disease

Irene Bolea, Jordi Juárez-Jiménez, Cristóbal De Los Ríos, Mourad Chioua, Ramón Pouplana, F Javier Luque, Mercedes Unzeta*, José Marco-Contelles, Abdelouahid Samadi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

A new family of multitarget 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 benzylpiperidine 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 (IC 50 = 5.2 ± 1.1 nM) and MAO-B (IC 50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC 50 = 0.35 ± 0.01 μM) and BuChE (IC 50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. (Figure presented)

Original languageEnglish
Pages (from-to)8251-8270
Number of pages20
JournalJournal of Medicinal Chemistry
Volume54
Issue number24
DOIs
Publication statusPublished - 22 Dec 2011

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