Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Design
2.2. Chemistry
2.3. Biological Evaluation
2.4. Molecular Modeling Studies
3. Materials and Methods
3.1. Chemistry
3.1.1. General Methods
3.1.2. General Procedure for the Synthesis of Compounds: 1–15 (Procedure A)
3.2. Biological Activity
3.2.1. In Vitro Inhibition of AChE and BuChE
3.2.2. In Vitro BACE-1 Inhibitory Activity
3.2.3. Inhibition of Aβ-Aggregation
3.3. Molecular Modeling
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the selected compounds (1–15) are available from the authors. |
Cmp. | R | n | eeAChE a | eqBuChE b | hBACE-1 c. | Aβ-Aggr. d |
---|---|---|---|---|---|---|
IC50 (µM) e/% Inh. f | IC50 (µM) e/% Inh. f | % Inh. f | % Inh. f | |||
1 | H | 1 | 11.5% ± 5.0% | 14.1% ± 3.3% | 37.3% ± 7.5% | <10% |
2 | 2-F | 1 | 28.1% ± 2.0% | 19.5% ± 2.0% | 39.6% ± 6.5% | 21.1% ± 6.6% |
3 | 2-CF3 | 1 | 11.8% ± 5.0% | <10% | 41.8% ± 4.5% | <10% |
4 | 3-Cl | 1 | <10% | 24.1% ± 4.7% | 34.1% ± 7.7% | <10% |
5 | 2-OMe | 1 | <10% | 7.86 ± 0.29 | 39.2% ± 9.2% | 19.9% ± 1.5% |
6 | 4-Me | 1 | <10% | 11.6% ± 3.3% | 45.0% ± 2.0% | <10% |
7 | 4-OMe | 1 | <10% | 19.1% ± 1.5% | 35.1% ± 10.0% | <10% |
8 | 2,4-diCl | 1 | <10% | 21.7% ± 1.0% | 37.2% ± 1.3% | <10% |
9 | H | 2 | <10% | <10% | <10% | <10% |
10 | 2-OMe | 2 | 32.7% ± 4.7% | 17.8% ± 2.0% | 24.4% ± 5.9% | <10% |
11 | 4-OMe | 2 | <10% | <10% | 34.8% ± 10.6% | <10% |
12 | H | 3 | 3.32 ± 0.15 | 14.1% ± 5.8% | 43.7% ± 6.9% | 24.9% ± 6.6% |
13 | 2-OMe | 3 | 11.07 ± 0.49 | 26.2% ± 9.7% | 37.1% ± 3.9% | <10% |
14 | H | 4 | 2.13 ± 0.07 | 36.0% ± 7.2% | 42.1% ± 10.7% | <10% |
15 | 2-OMe | 4 | 1.95 ± 0.06 | 36.0% ± 1.1% | 15.7% ± 1.3% | <10% |
Reference compounds | ||||||
Donepezil | 0.011 ± 0.0002 | 1.83 ± 0.04 | n.d. g | 13.8% ± 6.8 | ||
Tacrine | 0.023 ± 0.0004 | 0.015 ± 0.0001 | n.d. g | n.d. g | ||
Inhibitor IV h | n.d. g | n.d. g | 0.046 ± 0.001 i | n.d. g | ||
Resveratrol | n.d. g | n.d. g | n.d. g | 78.5% ± 5.2 |
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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
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 StylePanek, 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