(2018) Novel 3-phenylcoumarin–lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer's disease. Bioorganic Chemistry. pp. 223-234. ISSN 00452068 (ISSN)
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Abstract
New series of triazole-containing 3-phenylcoumarin–lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H 2 O 2 -induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC 50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ 1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H 2 O 2 -induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease. © 2018 Elsevier Inc.
| Item Type: | Article |
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| Keywords: | Alzheimer's disease Amyloid beta Antioxidant Coumarin Lipoic acid Neuroprotective activity Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Animals Cell Line, Tumor Dose-Response Relationship, Drug Humans Hydrogen Peroxide Molecular Structure Neuroprotective Agents PC12 Cells Peptide Fragments Protein Aggregates Rats Reactive Oxygen Species Structure-Activity Relationship 3 phenylcoumarin lipoic acid 5 (1,2 dithiolan 3 yl) n 1 3 4 (2 oxo 2h chromen 3 yl)phenoxy]propyl] 1h 1,2,3 triazol 4 yl]methyl]pentanamide 5 (1,2 dithiolan 3 yl) n 1 3 4 (3 oxo 3h benzofchromen 2 yl)phenoxypropyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 3 4 (6 nitro 2 oxo 2h chromen 3yl)phenoxypropyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 3 4 (8 methoxy 2 oxo 2h chromen 3 yl)phenoxypropyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 4 4 (2 oxo 2h chromen 3 yl)phenoxybutyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 4 4 (3 oxo 3h benzofchromen 2 yl)phenoxybutyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 4 4 (6 nitro 2 oxo 2h chromen 3yl)phenoxybutyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 4 4 (8 methoxy 2 oxo 2h chromen 3 yl)phenoxybutyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 5 4 (2 oxo 2h chromen 3 yl)phenoxypentyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 5 4 (3 oxo 3h benzofchromen 2 yl)phenoxypentyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 5 4 (6 bromo 2 oxo 2h chromen 3 yl)phenoxypentyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 5 4 (6 nitro 2 oxo 2h chromen 3 yl)phenoxypentyl 1h 1,2,3 triazol 4 ylmethylpentanamide 5 (1,2 dithiolan 3 yl) n 1 5 4 (8 methoxy 2 oxo 2h chromen 3 yl)phenoxypentyl 1h 1,2,3 triazol 4 ylmethylpentanamide amyloid beta protein1-42 ascorbic acid cholinesterase coumarin derivative donepezil n 1 3 4 (6 bromo 2 oxo 2h chromen 3 yl)phenoxypropyl 1h 1,2,3 triazol 4 ylmethyl 5 (1,2 dithiolan 3 yl)pentanamide n 1 4 4 (6 bromo 2 oxo 2h chromen 3 yl)phenoxybutyl 1h 1,2,3 triazol 4 ylmethyl 5 (1,2 dithiolan 3 yl)pentanamide neuroprotective agent quercetin reactive oxygen metabolite rifampicin thioctic acid triazole derivative unclassified drug amyloid beta protein amyloid beta-protein (1-42) peptide fragment protein aggregate antioxidant activity Article biological activity cell death cycloaddition drug design drug screening enzyme inhibition human human cell IC50 neuroprotection PC12 cell line priority journal protein aggregation SH-SY5Y cell line animal antagonists and inhibitors chemical structure chemistry dose response drug effect metabolism PC12 cell line (pheochromocytoma) rat structure activity relation synthesis tumor cell line |
| Page Range: | pp. 223-234 |
| Journal or Publication Title: | Bioorganic Chemistry |
| Volume: | 79 |
| Identification Number: | https://doi.org/10.1016/j.bioorg.2018.04.030 |
| ISSN: | 00452068 (ISSN) |
| Depositing User: | Mr mahdi sharifi |
| URI: | http://eprints.ssu.ac.ir/id/eprint/32100 |
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