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Synlett 2021; 32(20): 1987-2012
DOI: 10.1055/s-0040-1719823
DOI: 10.1055/s-0040-1719823
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Five-Membered-Ring-Fused Tacrines as Anti-Alzheimer’s Disease Agents
J.M.-C. dedicates this article to his colleagues and professors of the Department of Organic Chemistry (UCM, Madrid, Spain), who have contributed so much to his scientific career.
Abstract
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 Aβ1–40 aggregation in a statistically significant manner without affecting the Aβ1–40 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
Key words
Alzheimer’s disease - acetyl(butyryl)cholinesterase enzymes - acetyl(butyryl)cholinesterase inhibitors - Friedländer reactions - tacrines - multitarget small moleculesPublication History
Received: 09 May 2021
Accepted after revision: 24 June 2021
Article published online:
05 August 2021
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