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Eur J Med Chem. 2017 Feb 15;127:671-690. doi: 10.1016/j.ejmech.2016.10.036. Epub 2016 Oct 20.

Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil.

Author information

1
Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa.
2
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria, South Africa.
3
Pioneering Health Sciences, CSIR Biosciences, Meiring Naudé Road, Pretoria, South Africa.
4
Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa. Electronic address: Darren.riley@up.ac.za.

Abstract

A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50 value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50 of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50 of 0.05 ± 0.06 μM and an observed cytotoxicity IC50 of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.

KEYWORDS:

Acetylcholinesterase; Alzheimer's disease; Cytotoxicity; Donepezil; Piperidine

PMID:
27823887
DOI:
10.1016/j.ejmech.2016.10.036
[Indexed for MEDLINE]

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