Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy
Abstract
:1. Introduction
2. Design
3. Results and Discussion
3.1. Synthesis
3.2. Evaluation of AChE and BChE Inhibition Activity
3.3. Kinetic Study of AChE Inhibition
3.4. In Vitro Blood-Brain Barrier Permeation and Druglikeness
3.5. Cytotoxicity
3.6. In Silico Docking Studies
4. Materials and Methods
4.1. General Chemistry Methods
4.1.1. Preparation of 7-Methylenebicyclo[3.3.1]nonan-1-one (4)
4.1.2. Preparation of rac-7-Chloro-15-methyl-10-azatetracyclo[11.3.1.02,11.04,9]heptadeca-2(11),3,5,7,9,14-hexaen-3-amine hydrochloride ((±)-HupY·HCl)
4.1.3. Preparation of rac-6-Methoxy-15-methyl-10-azatetracyclo[11.3.1.02,11.04,9]heptadeca-2(11),3,5,7,9,14-hexaen-3-amine hydrochloride ((±)-1·HCl)
4.2. Biochemical Studies
4.2.1. In Vitro Anti-Cholinesterase Assay
4.2.2. Kinetic Study of AChE Inhibition
4.2.3. Determination of In Vitro Blood-Brain Barrier Permeation
4.2.4. Evaluation of Cytotoxicity by MTT Assay
4.3. Molecular Modeling Studies
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are available from the authors. |
Compound | IC50 ± SEM (µM) a | Selectiviy for hAChE b | |
---|---|---|---|
hAChE | hBChE | ||
(±)-1·HCl | 2.63 ± 0.36 | 3.76 ± 0.12 | 1.43 |
(±)-HupY·HCl | 0.00164 ± 0.00014 | 0.358 ± 0.025 | 218.29 |
THA | 0.32 ± 0.013 c | 0.08 ± 0.001 c | 0.68 |
7-MEOTA | 10.00 ± 0.974 c | 17.56 ± 0.795 c | 1.76 |
6-chlorotacrine | 0.02 ± 0.001 c | 1.78 ± 0.097 c | 100.68 |
Compound | BBB Penetration Estimation | |
---|---|---|
Pe ± SEM (10−6 cm·s−1) a | CNS (+/−) b | |
(±)-1·HCl | 7.64 ± 0.22 | CNS + |
(±)-HupY·HCl | 5.89 ± 0.36 | CNS + |
THA | 5.30 ± 0.20 c | CNS + |
Donepezil | 7.3 ± 0.9 | CNS + |
7-MEOTA | 6.50 ± 1.85 | CNS + |
6-chlorotacrine | 5.00 ± 0.45 c | CNS + |
Cefuroxim | 2.70 ± 0.1 | CNS − |
Piroxicam | 2.20 ± 0.15 | CNS − |
Compound | Physicochemical Properties | CNS MPO Score b | |||||
---|---|---|---|---|---|---|---|
ClogP a | ClogD7.4 a | TPSA a | MW a | HBD a | CpKa a | ||
(±)-1·HCl | 2.91 (3.58 ± 0.02) c | 1.56 (1.734) c | 49.39 | 280.36 | 2 | 8.91 (9.54 ± 0.02) c | 5.0 |
(±)-HupY·HCl | 3.67 | 2.95 | 40.16 | 285.79 | 2 | 8.07 | 5.0 |
THA | 2.63 | 1.25 | 40.16 | 199.27 | 2 | 8.95 | 4.7 |
7-MEOTA | 2.47 | 1.08 | 49.39 | 229.30 | 2 | 8.98 | 5.0 |
6-chlorotacrine | 3.23 | 2.41 | 40.16 | 233.72 | 2 | 8.20 | 5.1 |
Compound | IC50 ± SEM (µM) a | ||
---|---|---|---|
HepG2 | ACHN | SH-SY5Y | |
(±)-1·HCl | 14.91 ± 0.11 | 32.22 ± 0.72 | 17.84 ± 0.09 |
(±)-HupY·HCl | 15.87 ± 1.17 | 24.62 ± 0.32 | 17.49 ± 0.44 |
THA | 168.47 ± 3.63 | 155.20 ± 0.67 | 120.63 ± 1.97 |
7-MEOTA | 44.37 ± 3.35 | 49.27 ± 2.69 | 26.83 ± 1.04 |
6-chlorotacrine | 43.20 ± 1.17 | 55.11 ± 1.76 | 50.40 ± 1.28 |
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Mezeiova, E.; Korabecny, J.; Sepsova, V.; Hrabinova, M.; Jost, P.; Muckova, L.; Kucera, T.; Dolezal, R.; Misik, J.; Spilovska, K.; et al. Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy. Molecules 2017, 22, 1265. https://doi.org/10.3390/molecules22081265
Mezeiova E, Korabecny J, Sepsova V, Hrabinova M, Jost P, Muckova L, Kucera T, Dolezal R, Misik J, Spilovska K, et al. Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy. Molecules. 2017; 22(8):1265. https://doi.org/10.3390/molecules22081265
Chicago/Turabian StyleMezeiova, Eva, Jan Korabecny, Vendula Sepsova, Martina Hrabinova, Petr Jost, Lubica Muckova, Tomas Kucera, Rafael Dolezal, Jan Misik, Katarina Spilovska, and et al. 2017. "Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy" Molecules 22, no. 8: 1265. https://doi.org/10.3390/molecules22081265