Our endeavors in the design, synthesis, and biological assessment of five-membered-ring-fused tacrines as potential therapeutic agents for Alzheimer’s disease are summarized. Particularly, we have identified racemic 4-(2-methoxyphenyl)-3-methyl-2,4,6,7,8,9-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-5-amine, a pyranopyrazolotacrine, as having the best nontoxic profile at the highest concentrations used (300 μM); this allows cell viability, is less hepatotoxic than tacrine, and is a potent noncompetitive AChE inhibitor (IC₅₀ = 1.52 ± 0.49 μM). It is able to completely inhibit the EeAChE-induced Aβ_1–40 aggregation in a statistically significant manner without affecting the Aβ_1–40 self-aggregation at 25 μM, and shows strong neuroprotective effects (EC₅₀ = 0.82 ± 0.17 μM).

1 Introduction

2 Furo-, Thieno-, and Pyrrolotacrines

3 Pyrazolo-, Oxazolo-, and Isoxazolotacrines

4 Indolotacrines

5 Pyrano- and Pyridopyrazolotacrines

6 Conclusions and Outlook

总结了我们在五元环稠合他克林作为阿尔茨海默病潜在治疗剂的设计、合成和生物学评估方面的努力。特别是，我们已经确定了外消旋 4-(2-甲氧基苯基)-3-甲基-2,4,6,7,8,9-六氢吡唑并[4',3':5,6]吡喃并[2,3-b]喹啉-5-胺，一种吡喃吡唑他林，在使用的最高浓度 (300 μM) 下具有最佳的无毒特性；这允许细胞存活，比他克林具有更低的肝毒性，并且是一种有效的非竞争性 AChE 抑制剂 (IC ₅₀ = 1.52 ± 0.49 μM)。它能够以统计学上显着的方式完全抑制Ee AChE 诱导的 Aβ _1-40聚集而不影响 Aβ _1-40在 25 μM 时自聚集，并显示出强大的神经保护作用（EC ₅₀ = 0.82 ± 0.17 μM）。

1 简介

2 Furo-、Thieno- 和 Pyrrolotacrines

3 吡唑并、恶唑并和异恶唑他克林

4 吲哚酮

5 吡喃和吡啶并吡唑他克林

6 结论与展望