Five-Membered-Ring-Fused Tacrines as Anti-Alzheimer's Disease Agents

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 mu M); this allows cell viability, is less hepatotoxic than tacrine, and is a potent noncompetitive AChE inhibitor (IC50 = 1.52 +/- 0.49 mu M). It is able to completely inhibit the Ee AChE-induced A beta(1-40) aggregation in a statistically significant manner without affecting the A beta(1-40) self-aggregation at 25 mu M, and shows strong neuroprotective effects (EC50 = 0.82 +/- 0.17 mu M). 1 Introduction 2 Furo-, Thieno-, and Pyrrolotacrines 3 Pyrazolo-, Oxazolo-, and Isoxazolotacrines 4 Indolotacrines 5 Pyrano- and Pyridopyrazolotacrines 6 Conclusions and Outlook

Automated summary

The study summarizes the design, synthesis, and biological evaluation of novel five-membered-ring-fused tacrine compounds as potential therapeutic agents for Alzheimer's disease. Among them, a pyranopyrazolotacrine has shown promising pharmacological properties, such as high cell viability, low hepatotoxicity, and potent inhibition of AChE.