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 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

Key words

Alzheimer’s disease - acetyl(butyryl)cholinesterase enzymes - acetyl(butyryl)cholinesterase inhibitors - Friedländer reactions - tacrines - multitarget small molecules

Publication History

Received: 09 May 2021

Accepted after revision: 24 June 2021

Article published online:
05 August 2021

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