期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 19, 页码 5298-5307出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.07.053
关键词
Multitarget compounds; Phenolic antioxidants; Dual binding site AChE inhibitors; A beta aggregation inhibitors; Tau aggregation inhibitors
资金
- Ministerio de Ciencia e Innovacion (MICINN) [CTQ2011-22433, SAF2011-27642, SAF2009-10553]
- Ramon y Cajal Program [AGL2013-49083-C3-1-R]
- Instituto de Salud Carlos III, ISCIII (CIBERobn)
- Generalitat de Catalunya (GC) [2014SGR52, 2014SGR1189, 2014SGR773]
- GC
- IBUB
- Ramon y Cajal program of MICINN
- Juan de la Cierva program of Ministerio de Economia y Competitividad
- ICREA
Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS(center dot+), DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their A beta 42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent A beta 42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads. (C) 2014 Elsevier Ltd. All rights reserved.
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