Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 6, Pages 2257-2261Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.01.090
Keywords
Oxoisoaporphine derivatives; Synthesis; Acetylcholinesterase inhibitors; beta-amyloid aggregation
Categories
Funding
- National Basic Research Program of China [2010CB534911, 2012CB723501]
- National Natural Science Foundation of China [20861002]
- Natural Science Foundation of Guangxi Province [0832095, 0991003, 2010GXNSFF013001]
- Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University)
- Ministry of Education of China [07109001-07]
- Innovation project of Guangxi Graduate Education [2010106020703M68]
- BAGUI
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A series of novel oxoisoaporphine-based inhibitors (10-aminoalkylamino-1-azabenzanthrone ArNH(CH2)(n)(NRR2)-R-1) of acetylcholinesterase (AChE) has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE) and AChE-induced beta-amyloid (A beta) aggregation. The synthetic compounds exhibited high AChE inhibitory activity with IC50 values in the submicromolar range in most cases. Non-competitive binding mode was found for these derivatives by the graphical analysis of steady-state inhibition data. Moreover, all compounds exhibit significant inhibitory activity on AChE-induced A beta aggregation with inhibitory potency from 54.5% to 93.5%. Finally, six out of twelve synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. The result encourages us to study this class of compounds thoroughly and systematically. (C) 2012 Elsevier Ltd. All rights reserved.
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