Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer’s disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. H...

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Autores principales: Stavrakov, Georgi, Philipova, Irena, Lukarski, Atanas, Atanasova, Mariyana, Zheleva, Dimitrina, Zhivkova, Zvetanka D., Ivanov, Stefan, Atanasova, Teodora, Konstantinov, Spiro, Doytchinova, Irini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435983/
https://www.ncbi.nlm.nih.gov/pubmed/32717861
http://dx.doi.org/10.3390/molecules25153341
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author Stavrakov, Georgi
Philipova, Irena
Lukarski, Atanas
Atanasova, Mariyana
Zheleva, Dimitrina
Zhivkova, Zvetanka D.
Ivanov, Stefan
Atanasova, Teodora
Konstantinov, Spiro
Doytchinova, Irini
author_facet Stavrakov, Georgi
Philipova, Irena
Lukarski, Atanas
Atanasova, Mariyana
Zheleva, Dimitrina
Zhivkova, Zvetanka D.
Ivanov, Stefan
Atanasova, Teodora
Konstantinov, Spiro
Doytchinova, Irini
author_sort Stavrakov, Georgi
collection PubMed
description Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer’s disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.
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spelling pubmed-74359832020-08-24 Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors Stavrakov, Georgi Philipova, Irena Lukarski, Atanas Atanasova, Mariyana Zheleva, Dimitrina Zhivkova, Zvetanka D. Ivanov, Stefan Atanasova, Teodora Konstantinov, Spiro Doytchinova, Irini Molecules Article Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer’s disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL. MDPI 2020-07-23 /pmc/articles/PMC7435983/ /pubmed/32717861 http://dx.doi.org/10.3390/molecules25153341 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Stavrakov, Georgi
Philipova, Irena
Lukarski, Atanas
Atanasova, Mariyana
Zheleva, Dimitrina
Zhivkova, Zvetanka D.
Ivanov, Stefan
Atanasova, Teodora
Konstantinov, Spiro
Doytchinova, Irini
Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
title Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
title_full Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
title_fullStr Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
title_full_unstemmed Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
title_short Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
title_sort galantamine-curcumin hybrids as dual-site binding acetylcholinesterase inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435983/
https://www.ncbi.nlm.nih.gov/pubmed/32717861
http://dx.doi.org/10.3390/molecules25153341
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