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Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Mar 15; Vol. 25 (6), pp. 1997-2009. Date of Electronic Publication: 2017 Feb 14. - Publication Year :
- 2017
-
Abstract
- 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 Cu <superscript>2+</superscript> -induced Aβ <subscript>1-42</subscript> aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC <subscript>50</subscript> =0.59±0.02μM), MAO-A and MAO-B (IC <subscript>50</subscript> =1.01±0.02μM and 0.90±0.01μM respectively), excellent efficiency to block both self- and Cu <superscript>2+</superscript> -induced Aβ <subscript>1-42</subscript> aggregation (74.8±1.2% and 87.7±1.9% at 25μM, 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.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetylcholinesterase drug effects
Alzheimer Disease enzymology
Cell Line
Cholinesterase Inhibitors chemistry
Cholinesterase Inhibitors therapeutic use
Humans
Kinetics
Models, Molecular
Monoamine Oxidase Inhibitors chemistry
Monoamine Oxidase Inhibitors therapeutic use
Thioxanthenes chemistry
Thioxanthenes pharmacology
Thioxanthenes therapeutic use
Xanthones chemistry
Xanthones therapeutic use
Alzheimer Disease drug therapy
Amyloid beta-Peptides chemistry
Cholinesterase Inhibitors pharmacology
Monoamine Oxidase Inhibitors pharmacology
Xanthones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 25
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28237559
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.02.027