Abstract |
Seven tacrine/CHR21 conjugates have been designed and synthesized. Compound 8-7 was confirmed as the most active AChE inhibitor with IC50 value of 5.8 ± 1.4 nM, which was 7.72-fold stronger than tacrine. It was also shown as a strong BuChE inhibitor (IC50 value of 3.7 ± 1.3 nM). 8-7 was clearly highlighted not only as an excellent ChEs inhibitor, but also as a good modulator on protein expression of AChE, p53, Bax, Bcl-2, LC3, p62, and ULK, indicating its functions against programmed cell apoptosis and decrease of autophagy. 8-7 significantly reversed the glutamate-induced dysfunctions including excessive calcium influx and release from internal organelles, overproduction of nitric oxide (NO) and Aβ high molecular weight oligomer. This compound can penetrate blood-brain barrier (BBB). The in vivo hepatotoxicity assay indicated that 8-7 was much less toxic than tacrine. Altogether, these data strongly support that 8-7 is a potential multitarget-directed ligand (MTDL) for treating Alzheimer's disease (AD).
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Authors | Rongtian Lin, Shuwen Rao, Yanbing Li, Lei Zhang, Liyu Xu, Yepu He, Zhijun Liu, Heru Chen |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 211
Pg. 113067
(Feb 05 2021)
ISSN: 1768-3254 [Electronic] France |
PMID | 33338868
(Publication Type: Journal Article)
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Copyright | Copyright © 2020 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Iridoids
- Tacrine
- genipin
- Acetylcholinesterase
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Topics |
- Acetylcholinesterase
(pharmacology, therapeutic use)
- Alzheimer Disease
(drug therapy, pathology)
- Autophagy
- Drug Design
- Humans
- Iridoids
(pharmacology, therapeutic use)
- Molecular Structure
- Structure-Activity Relationship
- Tacrine
(pharmacology, therapeutic use)
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