Synthesis and Cholinesterase Inhibitory Activity of N-Phosphorylated/ N-Tiophosphorylated Tacrine.
Alzheimer's disease
Tacrine
cholinesterase inhibitors
molecular docking
neurodegenerative
disorder
phosphate analogs
Journal
Medicinal chemistry (Shariqah (United Arab Emirates))
ISSN: 1875-6638
Titre abrégé: Med Chem
Pays: Netherlands
ID NLM: 101240303
Informations de publication
Date de publication:
2020
2020
Historique:
received:
10
04
2019
revised:
01
07
2019
accepted:
01
07
2019
pubmed:
17
7
2019
medline:
3
6
2021
entrez:
17
7
2019
Statut:
ppublish
Résumé
Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease. Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer's disease (AD) agents. 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS. The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition. All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).
Sections du résumé
BACKGROUND
BACKGROUND
Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease.
OBJECTIVE
OBJECTIVE
Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer's disease (AD) agents.
METHODS
METHODS
9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS.
RESULTS
RESULTS
The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition.
CONCLUSION
CONCLUSIONS
All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).
Identifiants
pubmed: 31309898
pii: MC-EPUB-99669
doi: 10.2174/1573406415666190716115524
doi:
Substances chimiques
Cholinesterase Inhibitors
0
Tacrine
4VX7YNB537
Acetylcholinesterase
EC 3.1.1.7
Butyrylcholinesterase
EC 3.1.1.8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
947-957Informations de copyright
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