Design, Synthesis and Evaluation of Novel Tacrine-Ferulic Acid Hybrids as Multifunctional Drug Candidates against Alzheimer’s Disease
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. AChE and BuChE Inhibitory Activities
2.3. Inhibition of Self-Induced Aβ (1–42) Aggregation
2.4. Cu(II)-Chelating Properties
2.5. Kinetic Study of AChE Inhibition
2.6. Protective Effects of 8d on Aβ-Induced Neurotoxicity
3. Experimental Section
3.1. General Experimental Procedures
3.2. Synthesis
3.2.1. Procedure for the Preparation of (E)-Methyl 3-(4-hydroxy-3-methoxy-phenyl)acrylate (2)
3.2.2. Procedure for the Preparation of Ferulic Acid Derivatives (3a–e)
3.2.3. Procedure for the Preparation of 9-Amino-1,2,3,4-tetrahydroacridine (5)
3.2.4. Procedure for the Preparation of 2-Chloro-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide (6)
3.2.5. Procedure for the Preparation of 2-(Piperazin-1-yl)-N-(1,2,3,4-tetrahydro -acridin-9-yl)acetamide (7)
3.2.6. Procedure for the Preparation of TFAs 8a–e
3.3. AChE and BuChE Inhibitory Activity Assay
3.4. Inhibition of Aβ (1–42) Self-Induced Aggregation Assay
3.5. Cu2+-Chelating Properties Assay
3.6. Kinetic Analysis of AChE Inhibition
3.7. Cell Culture and Viability Assay
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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- Sample Availability: Samples of the compounds 8a–8e are available from the authors.
Compound | IC50 (nM) AChE a | IC50 (nM) BuChE b | Selectivity Index c | Aβ (1–42) Aggregation Inhibition (%) d | |
---|---|---|---|---|---|
| 8a | 306.5 ± 12.4 | 202.9 ± 35.7 | 0.660 | 26.1 ± 4.5 |
8b | 90.3 ± 7.3 | 119.7 ± 12.5 | 1.326 | 19.5 ± 2.7 | |
8c | 52.7 ± 8.2 | 215.4 ± 33.7 | 4.087 | 18.5 ± 4.0 | |
8d | 61.7 ± 5.2 | 106.9 ± 13.1 | 1.733 | 37.2 ± 0.9 | |
8e | 184.1 ± 15.2 | 195.7 ± 3.5 | 1.059 | 35.1 ± 3.2 | |
tacrine | 151.1 ± 10.3 | 27.6 ± 7.3 | 0.182 | n.t. e | |
curcumin | n.t. | n.t. | n.t. | 37.3 ± 1.2 | |
ferulic acid | n.t. | n.t. | n.t. | 36.5 ± 3.6 |
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Fu, Y.; Mu, Y.; Lei, H.; Wang, P.; Li, X.; Leng, Q.; Han, L.; Qu, X.; Wang, Z.; Huang, X. Design, Synthesis and Evaluation of Novel Tacrine-Ferulic Acid Hybrids as Multifunctional Drug Candidates against Alzheimer’s Disease. Molecules 2016, 21, 1338. https://doi.org/10.3390/molecules21101338
Fu Y, Mu Y, Lei H, Wang P, Li X, Leng Q, Han L, Qu X, Wang Z, Huang X. Design, Synthesis and Evaluation of Novel Tacrine-Ferulic Acid Hybrids as Multifunctional Drug Candidates against Alzheimer’s Disease. Molecules. 2016; 21(10):1338. https://doi.org/10.3390/molecules21101338
Chicago/Turabian StyleFu, Yingbo, Yu Mu, Hui Lei, Pu Wang, Xin Li, Qiao Leng, Li Han, Xiaodan Qu, Zhanyou Wang, and Xueshi Huang. 2016. "Design, Synthesis and Evaluation of Novel Tacrine-Ferulic Acid Hybrids as Multifunctional Drug Candidates against Alzheimer’s Disease" Molecules 21, no. 10: 1338. https://doi.org/10.3390/molecules21101338