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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 [Elektronski vir]Panek, Dawid ...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.Source: Molecules [Elektronski vir]. - ISSN 1420-3049 (Vol. 23, iss. 2, 2018, str. 1-15)Type of material - e-articlePublish date - 2018Language - englishCOBISS.SI-ID - 4473713
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http://www.mdpi.com/1420-3049/23/2/347Prost dostop
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DOI
Author
Panek, Dawid |
Więckowska, Anna |
Pasieka, Anna |
Godyń, Justyna |
Jończyk, Jakub |
Bajda, Marek |
Knez, Damijan, farmacevt |
Gobec, Stanislav, 1970- |
Malawska, Barbara
Topics
Alzheimerjeva bolezen |
isoindoline-1,3-dione derivatives |
cholinesterase inhibitors |
BACE-1 inhibitors |
Abeta-aggregation |
molecular modeling |
multiple anti-Alzheimer's ligands
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Panek, Dawid | |
Więckowska, Anna | |
Pasieka, Anna | |
Godyń, Justyna | |
Jończyk, Jakub | |
Bajda, Marek | |
Knez, Damijan, farmacevt | 36438 |
Gobec, Stanislav, 1970- | 15284 |
Malawska, Barbara |
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