Development of 5-hydroxyl-1-azabenzanthrone derivatives as dual binding site and selective acetylcholinesterase inhibitors.
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| Abstract |
A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC50 = 0.045 μM; eeBuChE IC50 = 19.68 μM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity. Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16, which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil. In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability.
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| Authors | Xiaona Sun, Yujin Wang, Zhichao Lei, Shasha Yue, Li Chen, Jianbo Sun |
| Journal | European journal of medicinal chemistry (Eur J Med Chem) Vol. 234 Pg. 114210 (Apr 15 2022) ISSN: 1768-3254 [Electronic] France |
| PMID | 35303485 (Publication Type: Journal Article) |
| Copyright | Copyright © 2022 Elsevier Masson SAS. All rights reserved. |
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