Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents

Panek, Dawid (author), Więckowska, Anna (author), Pasieka, Anna (author), Godyń, Justyna (author), Jończyk, Jakub (author), Bajda, Marek (author), Knez, Damijan (author), Gobec, Stanislav (author), Malawska, Barbara (author)

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

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