Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

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 shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vi...

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Published in:Bioorganic & medicinal chemistry 2014-10
Main Authors: Pérez-Areales, F. Javier, Di Pietro, Ornella, Espargaró Colomé, Alba, Vallverdú i Queralt, Anna, Galdeano Cantador, Carlos, Ragusa, Ilaria M, Viayna, Elisabet, Guillou, Catherine, Clos Guillén, M. Victòria, Pérez Fernández, Belén, Sabaté Lagunas, Raimon, Lamuela Raventós, Rosa Ma, Luque Garriga, F. Xavier, Muñoz-Torrero López-Ibarra, Diego
Format: Article
Language:English
Subjects:
Alzheimer's disease
Antioxidants
Disseny de medicaments
Drug design
Enzyme inhibitors
Inhibidors enzimàtics
Malaltia d'Alzheimer
Peptides
Pèptids
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Summary: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 shogaolhuprine 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 shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.
ISSN:0968-0896