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

• DOI: 10.1021/jm200853t
• Publication Date: 2011-10-24T09:08:05Z
• Authors: Irene Bolea; Jordi Juárez-Jiménez; Cristóbal de los ...; Mourad Chioua; Ramón Pouplana; F. Javier Luque; Mercedes Unzeta; José Marco-Contelles; Abdelouahid Samadi
• Keywords: Moiety; Butyrylcholinesterase; IC50; Linker; Molecular model

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well monoamino oxidase (MAO) B, has been synthesized. Novel compounds (3–9) have designed using a conjunctive approach that combines the benzylpiperidine moiety AChE inhibitor donepezil (1) indolyl propargylamino MAO 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 potent both MAO-A (IC50 = 5.2 ± 1.1 nM) MAO-B 43 8.0 moderately 0.35 0.01 μM) BuChE 0.46 0.06 μM). Moreover, molecular modeling kinetic studies support dual binding site AChE, which explains inhibitory effect exerted on Aβ aggregation. Overall, results suggest are drug candidates potential impact for Alzheimer's disease therapy.