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Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors.

ABSTRACT: 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.

SUBMITTER: Stavrakov G

PROVIDER: S-EPMC7435983 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors.

Stavrakov Georgi G Philipova Irena I Lukarski Atanas A Atanasova Mariyana M Zheleva Dimitrina D Zhivkova Zvetanka D ZD Ivanov Stefan S Atanasova Teodora T Konstantinov Spiro S Doytchinova Irini I

Molecules (Basel, Switzerland) 20200723 15

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 ...[more]

PMID: 32717861

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