Bioorganic & Medicinal Chemistry 2014-10-01

Shogaol-huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties.

F Javier Pérez-Areales, Ornella Di Pietro, Alba Espargaró, Anna Vallverdú-Queralt, Carles Galdeano, Ilaria M Ragusa, Elisabet Viayna, Catherine Guillou, M Victòria Clos, Belén Pérez, Raimon Sabaté, Rosa M Lamuela-Raventós, F Javier Luque, Diego Muñoz-Torrero

Index: Bioorg. Med. Chem. 22(19) , 5298-307, (2014)

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Abstract

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.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 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 Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.Copyright © 2014 Elsevier Ltd. All rights reserved.