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Donepezil Derivatives Targeting Amyloid-β Cascade in Alzheimer's Disease

[ Vol. 16 , Issue. 9 ]

Author(s):

Eva Mezeiova, Katarina Chalupova, Eugenie Nepovimova, Lukas Gorecki, Lukas Prchal, David Malinak, Kamil Kuca, Ondrej Soukup and Jan Korabecny*   Pages 772 - 800 ( 29 )

Abstract:


Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.

Keywords:

Acetylcholinesterase, Alzheimer`s disease, amyloid-β, biometal, beta-secretase 1, butyrylcholinesterase, multitarget directed ligands, neuroprotection.

Affiliation:

Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove



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