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

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 beta-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human %-secretase (hBACE-1), and beta-amyloid (A beta-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 microM), hBACE-1 (43.7% at 50 microM), and A beta-aggregation (24.9% at 10 microM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes acetylcholinesterase and beta-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: beta-secretase and A beta-aggregation.

Keywords

isoindoline-1,3-dione derivatives;cholinesterase inhibitors;BACE-1 inhibitors;Abeta-aggregation;molecular modeling;multiple anti-Alzheimer's ligands;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 616.894:615
COBISS: 4473713 Link will open in a new window
ISSN: 1420-3049
Views: 222
Downloads: 173
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Other data

Secondary language: Slovenian
Secondary keywords: Alzheimerjeva bolezen;
Type (COBISS): Article
Pages: str. 1-15
Volume: ǂVol. ǂ23
Issue: ǂiss. ǂ2
Chronology: 2018
DOI: 10.3390/molecules23020347
ID: 13641446