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Title: Synthesis and Biological Evaluation of New Donepezil-based Benzylamine Derivatives As Multiple Ligands Targeting Cholinesterases and Amyloid Beta


Alzheimer’s disease is a complex and fatal neurodegenerative disorder which still requires an effective therapy. We aimed to discover novel anti-Alzheimer’s agents: multiple ligands targeting cholinesterases and amyloid beta. Using donepezil as a starting point, we designed new series of compounds with a benzylamine pharmacophore – an analogue of a benzylpiperidine moiety in donepezil – responsible for interactions with the catalytic anionic site of acetylcholinesterase. In the second part of the target compounds, we introduced different heteroaromatic moieties – responsible for interactions with the peripheral anionic site of the enzyme – namely phthalimide, isoindolin-1-one, isoindoline and saccharin. Both fragments were connected by alkyl linkers of different lengths. Further modifications included introduction of fluorine and chlorine atoms into a phenyl ring of benzylamine. On the basis of biological evaluation results, we found the structural requirements for potent acetylcholinesterase inhibition and identified multiple ligands among the target compounds. We selected two lead compounds: 18 and 71 for further development. Compound 18, in addition to being a moderate human acetylcholinesterase inhibitor (hAChE IC50 = 0.268 μM), possesses other properties, such as the strong ability to inhibit self-induced Aβ1-42 aggregation (65.96% at 10 μM) and a neuroprotective effect against Aβ1-42 cytotoxicity at 1 and 3 μM. Compound 71 was found to be the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50 = 0.033 μM) and a moderate amyloid beta aggregation inhibitor (22.19 at 10 μM). Extended biological assays revealed that these compounds act as non-competitive acetylcholinesterase inhibitors and are able to cross the blood brain barrier in vitro.

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Level of degree:

2 - studia doktoranckie

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Jagiellonian University. Medical College. Faculty of Pharmacy. Chair of Pharmaceutical Chemistry. Department of Physicochemical Drug Analysis.


Barbara Malawska

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Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

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Last modified:

May 24, 2021

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Mar 20, 2018

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Edition name Date
ZB-126809 May 24, 2021


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