期刊
ACS CHEMICAL NEUROSCIENCE
卷 9, 期 5, 页码 1074-1094出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00461
关键词
Alzheimer's disease; multifunctional agents; butyrylcholinesterase inhibitors; BACE-1 inhibitors; A beta aggregation; tau aggregation; molecular docking
资金
- National Science Center of Poland [UMO-2016/21/B/NZ7/01744, UMO-2016/21/N/NZ7/03288]
- European Cooperation in Science and Technology COST Action [CA15135]
- Slovenian Research Agency [P1-0208, L1-8157]
The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, beta-secretase, amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of beta-secretase (IC50 hBACE-1 = 41.60 mu M), inhibition of amyloid beta aggregation (IC50, beta = 3.09 mu M), inhibition of tau aggregation (55% at 10 mu M); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 (hBuchE) = 7.22 mu M). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.
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