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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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/15/3341 |
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| author | Georgi Stavrakov Irena Philipova Atanas Lukarski Mariyana Atanasova Dimitrina Zheleva Zvetanka D. Zhivkova Stefan Ivanov Teodora Atanasova Spiro Konstantinov Irini Doytchinova |
| author_facet | Georgi Stavrakov Irena Philipova Atanas Lukarski Mariyana Atanasova Dimitrina Zheleva Zvetanka D. Zhivkova Stefan Ivanov Teodora Atanasova Spiro Konstantinov Irini Doytchinova |
| author_sort | Georgi Stavrakov |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T18:16:30Z |
| format | Article |
| id | doaj.art-f969c5d0d71942dfbbc39b700cdb4e01 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T18:16:30Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f969c5d0d71942dfbbc39b700cdb4e012023-11-20T07:40:24ZengMDPI AGMolecules1420-30492020-07-012515334110.3390/molecules25153341Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase InhibitorsGeorgi Stavrakov0Irena Philipova1Atanas Lukarski2Mariyana Atanasova3Dimitrina Zheleva4Zvetanka D. Zhivkova5Stefan Ivanov6Teodora Atanasova7Spiro Konstantinov8Irini Doytchinova9Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaInstitute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaFaculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaGalantamine (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.https://www.mdpi.com/1420-3049/25/15/3341virtual screeningmolecular dockingneurotoxicityADMEBBB permeability |
| spellingShingle | Georgi Stavrakov Irena Philipova Atanas Lukarski Mariyana Atanasova Dimitrina Zheleva Zvetanka D. Zhivkova Stefan Ivanov Teodora Atanasova Spiro Konstantinov Irini Doytchinova Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors Molecules virtual screening molecular docking neurotoxicity ADME BBB permeability |
| 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 | virtual screening molecular docking neurotoxicity ADME BBB permeability |
| url | https://www.mdpi.com/1420-3049/25/15/3341 |
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