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New Tacrine–4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties

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María Isabel Fernández-Bachiller‡§, Concepción Pérez‡, Leticia Monjas‡, Jörg Rademann§

, and María Isabel Rodríguez-Franco*‡

^‡ Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain

^§ Medicinal Chemistry, Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle Strasse 10, 13125 Berlin, Germany

Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Brüderstrasse 34, 04103 Leipzig, Germany

J. Med. Chem., 2012, 55 (3), pp 1303–1317

DOI: 10.1021/jm201460y

Publication Date (Web): January 13, 2012

*Phone: 34-91-5622900. Fax: 34-91-5644853. E-mail: IsabelRguez@iqm.csic.es.

Section:

Alkaloids

Abstract

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer’s disease (AD), a new family of tacrine–4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine–4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.

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History

Published In Issue February 09, 2012
Article ASAPJanuary 27, 2012
Just Accepted ManuscriptJanuary 13, 2012
Received: October 28, 2011

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New Tacrine–4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties