Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-<i>O</i>-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes respons...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/23/12/3252 |
| _version_ | 1811232212851359744 |
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| author | Keith D. Green Marina Y. Fosso Sylvie Garneau-Tsodikova |
| author_facet | Keith D. Green Marina Y. Fosso Sylvie Garneau-Tsodikova |
| author_sort | Keith D. Green |
| collection | DOAJ |
| description | A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-<i>O</i>-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of <i>Ee</i>AChE (IC<sub>50</sub> = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and <i>Ef</i>BChE (IC<sub>50</sub> = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against <i>Hs</i>AChE and was found to be even more active than donepezil and inhibited <i>Hs</i>AChE better than <i>Ee</i>AChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme. |
| first_indexed | 2024-04-12T10:59:40Z |
| format | Article |
| id | doaj.art-0195ac3bb27a4debab6eadbdfa98a431 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T10:59:40Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-0195ac3bb27a4debab6eadbdfa98a4312022-12-22T03:35:59ZengMDPI AGMolecules1420-30492018-12-012312325210.3390/molecules23123252molecules23123252Multifunctional Donepezil Analogues as Cholinesterase and BACE1 InhibitorsKeith D. Green0Marina Y. Fosso1Sylvie Garneau-Tsodikova2Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USAA series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-<i>O</i>-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of <i>Ee</i>AChE (IC<sub>50</sub> = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and <i>Ef</i>BChE (IC<sub>50</sub> = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against <i>Hs</i>AChE and was found to be even more active than donepezil and inhibited <i>Hs</i>AChE better than <i>Ee</i>AChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme.https://www.mdpi.com/1420-3049/23/12/3252Alzheimer’s diseaseacetylcholinesterasebutyrylcholinesteraseβ-secretaseinhibitors |
| spellingShingle | Keith D. Green Marina Y. Fosso Sylvie Garneau-Tsodikova Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors Molecules Alzheimer’s disease acetylcholinesterase butyrylcholinesterase β-secretase inhibitors |
| title | Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors |
| title_full | Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors |
| title_fullStr | Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors |
| title_full_unstemmed | Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors |
| title_short | Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors |
| title_sort | multifunctional donepezil analogues as cholinesterase and bace1 inhibitors |
| topic | Alzheimer’s disease acetylcholinesterase butyrylcholinesterase β-secretase inhibitors |
| url | https://www.mdpi.com/1420-3049/23/12/3252 |
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