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: 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: 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: 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: 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).