Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 2, Pages 763-770Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.12.022
Keywords
Tacrine hybrids; Anti-Alzheimer agent; Acetylcholinesterase; Butyrylcholinesterase; Self-induced A beta aggregation
Funding
- Natural Science Foundation of China [U0832005, 90813011, 20772159, 81001400]
- Science Foundation of Guangzhou [2009A1-E011-6]
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A new series of tacrine-multialkoxybenzene hybrids (9a-9n) were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced beta-amyloid (A beta) aggregation. All the synthesized compounds had high acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity with IC50 values at the nanomolar range, which were much better than tacrine alone. A Lineweaver-Burk plot and molecular modeling study showed that these hybrids targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compounds 9a-9f with methylenedioxybenzene moiety showed higher self-induced A beta aggregation inhibitory activity than a reference compound, curcumin. These compounds could be selected as multi-potent agents for further investigation to treat AD. (C) 2010 Elsevier Ltd. All rights reserved.
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