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

Maria do Carmo Carreiras; José Marco-Contelles

doi:10.1055/s-0040-1719823

Synlett, Inhaltsverzeichnis

Synlett 2021; 32(20): 1987-2012
DOI: 10.1055/s-0040-1719823

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

Maria do Carmo Carreiras∗

^aResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal

,

José Marco-Contelles

^bLaboratory of Medicinal Chemistry (IQOG, CSIC), Juan de la Cierva 3, 28006-Madrid, Spain

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Abstract

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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

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Referenzen

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