Design, synthesis and evaluation of novel 5, 6, 7-trimethoxyflavone–6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer's disease
Abstract
A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BuChE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Aβ) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8 nM, potent inhibition of self-induced Aβ1-42 aggregation with inhibition ratio of 33.8% at 25 μM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD.
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Oxidative stress is a critical component of pathogenesis in AD.
“Also, oxidative stress is a critical component of pathogenesis in AD (3,4)”
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- Authors
- Liao, S., Deng, H., Huang, S., Yang, J., Wang, S., Yin, B., Zheng, T., Zhang, D., Liu, J., Gao, G., Ma, J., & Deng, Z.
- Affiliations
- Wenzhou Medical University (CN)
- Corresponding author
- Deng, Hui
- Ma, Jianfeng
- Deng, Zhennan
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 25
- Issue
- 7
- Pages
- 1541-1545
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2018701037
- Cited by
- 24
- References
- 25
- Citations by year
- 2024: 4 · 2023: 3 · 2022: 1 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 5
- FWCI
- 2.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81100782)
- Zhejiang Provincial Natural Science Foundation of China (Y2110400)
- Health Bureaue of Zhejiang Province (2012KYA128)
- Wenzhou Municipal Science and Technology Bureau Foundation of China (Y20140112)
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Synthesis of Organic Compounds
- Keywords
- Alzheimer's disease, acetylcholinesterase inhibition, butyrylcholinesterase selectivity, antioxidant activity, amyloid beta aggregation inhibition, amyloid-beta 42, neuroprotection, blood-brain barrier permeability
- MeSH terms
- Acetylcholinesterase, Alzheimer Disease, Animals, Antioxidants, Butyrylcholinesterase, Cell Survival, Cholinesterase Inhibitors, Dose-Response Relationship, Drug, Electrophorus, Structure-Activity Relationship, Tacrine, Drug Design, Molecular Structure, PC12 Cells, Equidae, Flavones, Rats
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