Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease
Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer’s disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compoun...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2313682 |
| _version_ | 1826919907043835904 |
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| author | Chuanyu Yu Xueyan Liu Bingxiang Ma Jiexin Xu Yiquan Chen Chaoxian Dai Huaping Peng Daijun Zha |
| author_facet | Chuanyu Yu Xueyan Liu Bingxiang Ma Jiexin Xu Yiquan Chen Chaoxian Dai Huaping Peng Daijun Zha |
| author_sort | Chuanyu Yu |
| collection | DOAJ |
| description | Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer’s disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD. |
| first_indexed | 2024-03-08T00:19:53Z |
| format | Article |
| id | doaj.art-8f19dbb6543e45b58f07e8dc5d990a6c |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-02-17T13:20:19Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-8f19dbb6543e45b58f07e8dc5d990a6c2024-12-26T09:30:44ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2313682Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s diseaseChuanyu Yu0Xueyan Liu1Bingxiang Ma2Jiexin Xu3Yiquan Chen4Chaoxian Dai5Huaping Peng6Daijun Zha7Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, ChinaButyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer’s disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.https://www.tandfonline.com/doi/10.1080/14756366.2024.2313682Alzheimer’s diseasebutyrylcholinesterase inhibitorsanti-neuroinflammationpyranone-carbamate derivativescognitive improvement |
| spellingShingle | Chuanyu Yu Xueyan Liu Bingxiang Ma Jiexin Xu Yiquan Chen Chaoxian Dai Huaping Peng Daijun Zha Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease Journal of Enzyme Inhibition and Medicinal Chemistry Alzheimer’s disease butyrylcholinesterase inhibitors anti-neuroinflammation pyranone-carbamate derivatives cognitive improvement |
| title | Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease |
| title_full | Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease |
| title_fullStr | Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease |
| title_full_unstemmed | Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease |
| title_short | Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease |
| title_sort | novel anti neuroinflammatory pyranone carbamate derivatives as selective butyrylcholinesterase inhibitors for treating alzheimer s disease |
| topic | Alzheimer’s disease butyrylcholinesterase inhibitors anti-neuroinflammation pyranone-carbamate derivatives cognitive improvement |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2313682 |
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