2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Pharmacological Evaluation
2.2.1. Studies of AChE/BChE Inhibition
2.2.2. Studies of Molecular Modeling
2.2.3. Radiolabeling with 99mTc and Biodistribution Studies in Rats
3. Experimental Section
3.1. Chemistry
3.1.1. 6-Hydrazinopyridine-3-carboxylic Acid (1)
3.1.2. 6-BOC-hydrazinopyridine-3-carboxylic Acid (2)
3.1.3. 9-Chloro-2,3-dihydro-1H-cyclopenta[b]quinoline (3)
3.1.4. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)ethane-1,2-diamine (4a)
3.1.5. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)propane-1,3-diamine (4b)
3.1.6. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)butane-1,4-diamine (4c)
3.1.7. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)penthane-1,5-diamine (4d)
3.1.8. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)hexane-1,6-diamine (4e)
3.1.9. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)heptane-1,7-diamine (4f)
3.1.10. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)octane-1,8-diamine (4g)
3.1.11. N′-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-yl)nonane-1,9-diamine (4f)
3.1.12. N-{5-[2-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)ethylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5a)
3.1.13. N-{5-[3-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)propylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5b)
3.1.14. N-{5-[4-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)butylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5c)
3.1.15. N-{5-[5-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)pentylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5d)
3.1.16. N-{5-[6-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)hexylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5e)
3.1.17. N-{5-[7-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)heptylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5f)
3.1.18. N-{5-[8-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)octylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5g)
3.1.19. N-{5-[9-(2,3-Dihydro-1H-cyclopenta[b]quinolin-9-ylamino)nonylcarbamoyl]pyridin-2-yl} hydrazinecarboxylic Acid tert-Butyl Ester (5h)
3.1.20. 6-Hydrazino-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)Ethyl]nicotinamide hydrochloride (6a)
3.1.21. 6-Hydrazino-N-[3-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)propyl]nicotinamide hydrochloride (6b)
3.1.22. 6-Hydrazino-N-[4-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)butyl]nicotinamide hydrochloride (6c)
3.1.23. 6-Hydrazino-N-[5-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)pentyl]nicotinamide hydrochloride (6d)
3.1.24. 6-Hydrazino-N-[6-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)hexyl]nicotinamide hydrochloride (6e)
3.1.25. 6-Hydrazino-N-[7-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)heptyl]nicotinamide hydrochloride (6f)
3.1.26. 6-Hydrazino-N-[8-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)octyl]nicotinamide hydrochloride (6g)
3.1.27. 6-Hydrazino-N-[9-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)nonyl]nicotinamide hydrochloride (6h)
3.2. Biochemical Studies
3.3. Molecular Modeling
3.4. Spectrophotometric Experiments
3.5. Radiolabelling
- Mobile phase A: 0.9% NaCl, B: CH3CN.
- 1–25 min 50% B.
- 25–30 min 50%–100% B.
- 30–35 min 100% B.
- 35–40 min 100%–0% B.
- 0–10 min 0% B.
- 10–25 min 0%–100% B.
- 25–30 min 100% B.
- 30–35 min 100%–0% B.
3.6. Biodistribution Studies in Rats
3.6.1. Animals
3.6.2. Biodistribution in Rats
4. Conclusions
Acknowledgments
References
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Compound | AChE IC50, (nM) ± SEM a | BChE IC50, (nM) ± SEM b | Selectivity for AChE c | Selectivity for BChE d |
---|---|---|---|---|
6a | 31.50 ± 1.9 | 164.00 ± 1.6 | 5.21 | 0.19 |
6b | 19.30 ± 1.1 | 197.00 ± 3.4 | 10.21 | 0.10 |
6c | 22.40 ± 1.7 | 2650.00 ± 9.5 | 118.30 | 0.01 |
6d | 7.84 ± 2.2 | 4240.00 ± 2.2 | 540.82 | 0.00 |
6e | 41.60 ± 1.0 | 16600.00 ± 17.5 | 399.04 | 0.00 |
6f | 17.60 ± 0.8 | 22700.00 ± 20.6 | 1289.77 | 0.00 |
6g | 5.17 ± 1.4 | 19600.00 ± 16.4 | 3791.10 | 0.00 |
6h | 3.65 ± 0.5 | 17100.00 ± 21.3 | 4684.93 | 0.00 |
tacrine | 5.46 ± 1.0 | 2.44 ± 0.6 | 0.45 | 2.24 |
99mTc-6a (% Dose/g) | ||||
---|---|---|---|---|
Organs | 5 min | 60 min | 120 min | 24 h |
Blood | 0.850 ± 0.108 | 0.114 ± 0.015 | 0.091 ± 0.017 | 0.033 ± 0.004 |
Plasma | 0.921 ± 0.124 | 0.183 ± 0.024 | 0.150 ± 0.027 | 0.052 ± 0.003 |
Pancreas | 0.551 ± 0.109 | 0.117 ± 0.019 | 0.092 ± 0.015 | 0.067 ± 0.006 |
Liver | 5.752 ± 0.742 | 5.160 ± 0.586 | 5.630 ± 0.508 | 5.095 ± 0.478 |
Adrenals | 1.186 ± 0.231 | 0.900 ± 0.102 | 0.890 ± 0.040 | 0.793 ± 0.137 |
Kidney | 3.838 ± 0.264 | 1.556 ± 0.148 | 1.332 ± 0.209 | 1.026 ± 0.130 |
Lung | 3.497 ± 0.239 | 2.010 ± 0.323 | 1.824 ± 0.438 | 1.354 ± 0.066 |
Heart | 0.779 ± 0.078 | 0.241 ± 0.013 | 0.204 ± 0.025 | 0.147 ± 0.009 |
Spleen | 0.999 ± 0.218 | 1.840 ± 0.618 | 2.172 ± 0.391 | 2.631 ± 0.199 |
Stomach | 0.206 ± 0.044 | 0.469 ± 0.438 | 0.311 ± 0.153 | 0.571 ± 0.389 |
Intestine | 0.977 ± 0.313 | 4.242 ± 0.113 | 3.661 ± 1.491 | 0.196 ± 0.055 |
Colon | 0.108 ± 0.031 | 0.044 ± 0.003 | 1.566 ± 1.539 | 1.809 ± 0.976 |
Testes | 0.054 ± 0.004 | 0.033 ± 0.001 | 0.030 ± 0.005 | 0.022 ± 0.003 |
Skin | 0.290 ± 0.039 | 0.196 ± 0.017 | 0.169 ± 0.029 | 0.100 ± 0.010 |
Muscle | 0.157 ± 0.004 | 0.056 ± 0.007 | 0.048 ± 0.006 | 0.037 ± 0.005 |
Thyroid | 0.551 ± 0.040 | 0.225 ± 0.021 | 0.189 ± 0.009 | 0.124 ± 0.037 |
Brain | 0.049 ± 0.003 | 0.013 ± 0.001 | 0.014 ± 0.003 | 0.007 ± 0.001 |
Fat | 0.305 ± 0.060 | 0.120 ± 0.019 | 0.105 ± 0.017 | 0.070 ± 0.017 |
Femur | 0.330 ± 0.036 | 0.202 ± 0.015 | 0.218 ± 0.031 | 0.232 ± 0.037 |
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Szymański, P.; Lázničková, A.; Lázniček, M.; Bajda, M.; Malawska, B.; Markowicz, M.; Mikiciuk-Olasik, E. 2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution. Int. J. Mol. Sci. 2012, 13, 10067-10090. https://doi.org/10.3390/ijms130810067
Szymański P, Lázničková A, Lázniček M, Bajda M, Malawska B, Markowicz M, Mikiciuk-Olasik E. 2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution. International Journal of Molecular Sciences. 2012; 13(8):10067-10090. https://doi.org/10.3390/ijms130810067
Chicago/Turabian StyleSzymański, Paweł, Alice Lázničková, Milan Lázniček, Marek Bajda, Barbara Malawska, Magdalena Markowicz, and Elżbieta Mikiciuk-Olasik. 2012. "2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution" International Journal of Molecular Sciences 13, no. 8: 10067-10090. https://doi.org/10.3390/ijms130810067