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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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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 (dk_c)
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Year:2018
Publication status in journal:Published
Article version:Publisher's version of article
Number of pages:15 str.
Numbering:Vol. 23, iss. 2, art. 347
UDC:616.894:615
ISSN on article:1420-3049
DOI:10.3390/molecules23020347 This link opens in a new window
COBISS.SI-ID:4473713 This link opens in a new window
Publication date in RUL:05.10.2021
Views:193
Downloads:160
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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 This link opens in a new window

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

Document is financed by a project

Funder:Drugi - Drug financer ali več financerjev
Funding programme:National Science Center of Poland
Project number:UMO-2016/21/B/NZ7/01744

Funder:Drugi - Drug financer ali več financerjev
Funding programme:National Science Center of Poland
Project number:UMO-2016/21/N/NZ7/03288

Funder:Drugi - Drug financer ali več financerjev
Funding programme:COST
Project number:CA15135

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project number:P1-0208
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project number:L1-8157
Name:Razvoj multifunkcionalnih učinkovin za zdravljenje Alzheimerjeve bolezni

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