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Ta publikacja jest chroniona prawem autorskim. Dostęp z komputerów Biblioteki Medycznej UJ CM.

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

Autor:

Szałaj, Natalia

Data:

2015

Typ:

Praca doktorska

Abstrakt:

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.

Miejsce wydania:

Kraków

Stopień studiów:

2 - studia doktoranckie

Dyscyplina:

farmacja

Instytucja nadająca tytuł:

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

Promotor:

Barbara Malawska

Data wydania:

2015

Format:

application/pdf

Identyfikator:

oai:dl.cm-uj.krakow.pl:4232

Sygnatura:

ZB-126809

ControlNumberVIRTUA:

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Prawa dostępu:

tylko w bibliotece

Lokalizacja oryginału:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

Temat i słowa kluczowe:

Alzheimer’s disease multiple ligands cholinesterase inhibitors amyloid beta

Kolekcje, do których przypisany jest obiekt:

Data ostatniej modyfikacji:

24 maj 2021

Data dodania obiektu:

20 mar 2018

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10

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Wszystkie dostępne wersje tego obiektu:

http://dl.cm-uj.krakow.pl:8080/publication/4233

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Nazwa wydania Data
ZB-126809 24 maj 2021

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Adres

Biblioteka Medyczna
ul. Medyczna 7
30-688 Kraków

Telefon

12 658 72 56
517 385 669

E-Mail

Oddział Gromadzenia i Opracowania Zbiorów
cyfrowabm@cm-uj.krakow.pl

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