期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 139, 期 -, 页码 48-59出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.07.055
关键词
Monoamine oxidase inhibitors; Acetylcholinesterase inhibitors; Multi-target ligand design; Alzheimer's disease; Coumarin derivatives
资金
- National Natural Science Foundation of China [81403175, 81274200]
- Shanghai Committee of Science and Technology [14YF1411300]
- Shanghai Municipal Commission of Health and Family planning [20134Y053]
- Health and Family planning Commission of Jiangxi province [2016A048]
- Shanghai University of Traditional Chinese Medicine [2016YSN21]
- Research Fund for the Docoral Program of Shanghai [B201703]
Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and A beta (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 mu M for eeAChE; 2.32 mu M for eqBuChE; 1.57 mu M for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit A beta (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit. (C) 2017 Elsevier Masson SAS. All rights reserved.
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