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Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents
ID
Panek, Dawid
(
Author
),
ID
Więckowska, Anna
(
Author
),
ID
Pasieka, Anna
(
Author
),
ID
Godyń, Justyna
(
Author
),
ID
Jończyk, Jakub
(
Author
),
ID
Bajda, Marek
(
Author
),
ID
Knez, Damijan
(
Author
),
ID
Gobec, Stanislav
(
Author
),
ID
Malawska, Barbara
(
Author
)
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MD5: 0DEC31C48C934B9B622C5A52A9E37F71
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http://www.mdpi.com/1420-3049/23/2/347
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Abstract
The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human β-secretase (hBACE-1), and β-amyloid (Aβ-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC$_{50}$ = 3.33 µM), hBACE-1 (43.7% at 50 µM), and Aβ-aggregation (24.9% at 10 µM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes acetylcholinesterase and β-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: β-secretase and Aβ-aggregation.
Language:
English
Keywords:
isoindoline-1
,
3-dione derivatives
,
cholinesterase inhibitors
,
BACE-1 inhibitors
,
Aβ-aggregation
,
molecular modeling
,
multiple anti-Alzheimer's ligands
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
Publication status:
Published
Publication version:
Version of Record
Year:
2018
Number of pages:
15 str.
Numbering:
Vol. 23, iss. 2, art. 347
PID:
20.500.12556/RUL-131864
UDC:
616.894:615
ISSN on article:
1420-3049
DOI:
10.3390/molecules23020347
COBISS.SI-ID:
4473713
Publication date in RUL:
05.10.2021
Views:
911
Downloads:
264
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Record is a part of a journal
Title:
Molecules
Shortened title:
Molecules
Publisher:
MDPI
ISSN:
1420-3049
COBISS.SI-ID:
18462981
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:
07.02.2018
Secondary language
Language:
Slovenian
Keywords:
Alzheimerjeva bolezen
Projects
Funder:
Other - Other funder or multiple funders
Funding programme:
National Science Center of Poland
Project number:
UMO-2016/21/B/NZ7/01744
Funder:
Other - Other funder or multiple funders
Funding programme:
National Science Center of Poland
Project number:
UMO-2016/21/N/NZ7/03288
Funder:
Other - Other funder or multiple funders
Funding programme:
COST
Project number:
CA15135
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
ARRS - Slovenian Research Agency
Project number:
L1-8157
Name:
Razvoj multifunkcionalnih učinkovin za zdravljenje Alzheimerjeve bolezni
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