Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue -, Pages 540-553Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.03.051
Keywords
Alzheimer's disease; Coumarin; Tacrine; Metal chelator; Cholinesterase; beta-amyloid aggregation
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Funding
- Program for Changjiang Scholars and Innovative Research Team in University [IRT1193]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Simcere Pharmaceutical Group for graduate student at China Pharmaceutical University [CX11B-002XS]
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A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced,beta-amyloid (A beta) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 mu M) and A beta aggregation (67.8%, 20 mu M). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 mu M) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment. (C) 2013 Elsevier Masson SAS. All rights reserved.
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