Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 24, Pages 8251-8270Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm200853t
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Funding
- Ministerio de Ciencia e Innovacion [SAF2006-08764-C02-01, SAF2009-07271, SAF2008-05595]
- Generalitat de Catalunya [2009-SGR00298]
- Comunidad de Madrid [S/SAL-0275-2006]
- Institut de Salud Carlos III [Retic RENEVAS] [RD06/0026/1002]
- Fundacion CIEN [CP10/00531]
- COST Action [D34/0003/05]
- MICINN
- Instituto de Salud Carlos III
- Instituto de Salud Carlos III [FI10/00292]
- Departamento de Farmacologia y Terapeutica, Facultad de Medicina, Universidad Autonoma de Madrid, Spain
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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 (IC50 = 5.2 +/- 1.1 nM) and MAO-B (IC50 = 43 +/- 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 +/- 0.01 mu M) and BuChE (IC50 = 0.46 +/- 0.06 mu M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A beta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.
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