期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 6, 页码 1997-2009出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.02.027
关键词
Alzheimer's disease; Thioxanthone derivatives; Multifunctional agents; Acetylcholinesterase inhibitors; Anti-A beta aggregation; Monoamine oxidase inhibitors
资金
- Chinese National Natural Science Foundation [20872099]
- Research Fund for the Doctoral Program of Higher Education [20110181110079]
- National Science and Technology Major Project
- Key New Drug Creation and Manufacturing Program [2013ZX09301304-002]
A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self and Cu2+-induced A beta(1-42) aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50 = 0.59 +/- 0.02 mu M), MAO-A and MAO-B (IC50 = 1.01 +/- 0.02 mu M and 0.90 +/- 0.01 mu M respectively), excellent efficiency to block both self- and Cu2+-induced A beta(1-42) aggregation (74.8 +/- 1.2% and 87.7 +/- 1.9% at 25 mu M, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD. (C) 2017 Elsevier Ltd. All rights reserved.
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