Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives
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- 作者：Dr. Serena Montanari ; Prof. Manuela Bartolini ; Dr. Paolo Neviani ; Dr. Federica Belluti ; Prof. Silvia Gobbi ; Dr. Letizia Pruccoli ; Prof. Andrea Tarozzi ; Dr. Federico Falchi ; Prof. Vincenza Andrisano ; Dr. Przemysław Miszta ; Prof. Andrea Cavalli ; Prof. Sławomir Filipek ; Prof. Alessandra Bisi and Dr. Angela Rampa
- 刊名：ChemMedChem
- 出版年：2016
- 出版时间：June 20, 2016
- 年：2016
- 卷：11
- 期：12
- 页码：1296-1308
- 全文大小：7828K
- ISSN：1860-7187
文摘
Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3-(4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin-11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-6-{[5-(diethylamino)pentyl]oxy}-2H-chromen-2-one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Aβ42 self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent.