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Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer's Disease
E. Kohelová, R. Peřinová, N. Maafi, J. Korábečný, D. Hulcová, J. Maříková, T. Kučera, L. Martínez González, M. Hrabinova, K. Vorčáková, L. Nováková, A. De Simone, R. Havelek, L. Cahlíková,
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
GA UK Nr. 178518, SVV UK 260 412; 260 401; Progres/UK Q40 and Q42
Univerzita Karlova v Praze
00179906
University Hospital, Hradec Králové
CZ.02.1.01/0.0/0.0/18_069/0010046
European Union
Free Medical Journals od 1997
PubMed Central od 2001
Europe PubMed Central od 2001
ProQuest Central od 1997-01-01
Open Access Digital Library od 1997-01-01
Medline Complete (EBSCOhost) od 2009-03-01
Health & Medicine (ProQuest) od 1997-01-01
Odkazy
PubMed
30987121
DOI
10.3390/molecules24071307
Knihovny.cz E-zdroje
- MeSH
- alkaloidy amarylkovitých chemie metabolismus MeSH
- Alzheimerova nemoc metabolismus MeSH
- Amaryllidaceae chemie metabolismus MeSH
- fenantridiny chemie metabolismus MeSH
- GSK3B metabolismus MeSH
- hematoencefalická bariéra metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- permeabilita MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Twelve derivatives 1a-1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.
Centro de Investigaciones Biológicas CSIC Avenida Ramiro de Maeztu 9 28040 Madrid Spain
Department for Life Quality Studies University of Bologna Corso D'Augusto 237 47921 Rimini Italy
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- $a Kohelová, Eliška $u ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. kohelove@faf.cuni.cz.
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- $a Vorčáková, Katarina $u Deaprtment of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 95, 532 10 Pardubice, Czech Republic. katarina.vorcakova@upce.cz.
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