期刊
BIOORGANIC CHEMISTRY
卷 94, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103413
关键词
Ferulic acid deriveatives; Alzheimer's disease; Cholinesterase; A beta (1-42) aggregation; Multi-target-directed ligands; Molecular docking
资金
- National Natural Science Foundation of China [81872981, 81760622]
- Program of Shanghai Academic/Technology Research Leader [18XD1403700]
- National Scientific and Technological Major Special Project of China [2018ZX09201008-002]
- Youth Talent Sail Plan from the Shanghai Committee of Science and Technology [18YF1423600]
- development fund for Shanghai talents [2018105]
- Project of the Shanghai Municipal Commission of Health and Family Planning [2017YQ072, 201740152]
- Research Fund for the Doctoral Program of Shanghai [B201703]
- Undergraduate innovation project from Shanghai University of traditional Chinese Medicine [2019SHUTCM146]
- Xinglin Young Talent Program
A series of new ferulic acid derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer's disease. In vitro studies indicated that most compounds showed significant potency to inhibit self-induced beta-amyloid (A beta) aggregation and acetylcholinesterase (AChE), and had good antioxidant activity. Specifically, compound 4g exhibited the potent ability to inhibit cholinesterase (ChE) (IC50, 19.7 nM for hAChE and 0.66 mu M for hBuChE) and the good A beta aggregation inhibition (49.2% at 20 mu M), and it was also a good antioxidant (1.26 trolox equivalents). Kinetic and molecular modeling studies showed that compound 4g was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, compound 4g could remarkably increase PC12 cells viability in hydrogen peroxide-induced oxidative cell damage and A beta-induced cell damage. Finally, compound 4g had good ability to cross the BBB using the PAMPA-BBB assay. These results suggested that compound 4g was a promising multifunctional ChE inhibitor for the further investigation.
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