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 neuroblastomacell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).

背景：阿尔茨海默氏病（AD）是进行性和不可逆的神经退行性疾病。当前的药物疗法不能停止疾病的进展并且只能改善认知功能。因此，正在寻找新的药物来减缓疾病的发展。

目的：设计，合成新型的磷和硫代磷他克林衍生物7-14，并研究它们的生物学活性和分子模型，作为一种潜在的新型抗阿尔茨海默氏病（AD）药物。

方法：在碘化钠存在下，用丙烷-1,3-二胺处理9-氯代高辛，得到N1-（1,2,3,4-四氢ac啶-9-基）丙烷-1,3-二胺6。最后，用相应的酸酯或硫代酯处理，得到磷或硫代磷他克林衍生物7-14。通过1 H NMR，13 C NMR，31 P NMR和MS表征所有获得的最终结构。

结果：对接研究的结果表明，新设计的磷和硫代磷他克林类似物在理论上具有AChE和BChE结合能力。动力学研究表明，该系列中的8和12被证明是比他克林更有效的电鳗AChE（eeAChE）和人类（hAChE）抑制剂，其中8种和12种对eeAChE的抑制作用是参考药物的三倍。最高的BChE抑制作用显示11和13。对eeAChE，hAChE和BChE最具活性的化合物表现出混合的抑制作用。

结论：与他克林相比，所有新合成的化合物对神经母细胞瘤细胞系（SH-SY5Y）的毒性均较低。该系列的两个类似物7和9表现出缺乏针对肝细胞（hepG2）的细胞毒性。