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Article

Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents

1
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2018, 23(2), 347; https://doi.org/10.3390/molecules23020347
Received: 17 January 2018 / Revised: 1 February 2018 / Accepted: 3 February 2018 / Published: 7 February 2018
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 (IC50 = 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. View Full-Text
Keywords: isoindoline-1,3-dione derivatives; cholinesterase inhibitors; BACE-1 inhibitors; Aβ-aggregation; molecular modeling; multiple anti-Alzheimer’s ligands isoindoline-1,3-dione derivatives; cholinesterase inhibitors; BACE-1 inhibitors; Aβ-aggregation; molecular modeling; multiple anti-Alzheimer’s ligands
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MDPI and ACS Style

Panek, D.; Więckowska, A.; Pasieka, A.; Godyń, J.; Jończyk, J.; Bajda, M.; Knez, D.; Gobec, S.; Malawska, B. Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents. Molecules 2018, 23, 347. https://doi.org/10.3390/molecules23020347

AMA Style

Panek D, Więckowska A, Pasieka A, Godyń J, Jończyk J, Bajda M, Knez D, Gobec S, Malawska B. Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents. Molecules. 2018; 23(2):347. https://doi.org/10.3390/molecules23020347

Chicago/Turabian Style

Panek, Dawid, Anna Więckowska, Anna Pasieka, Justyna Godyń, Jakub Jończyk, Marek Bajda, Damijan Knez, Stanislav Gobec, and Barbara Malawska. 2018. "Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents" Molecules 23, no. 2: 347. https://doi.org/10.3390/molecules23020347

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