title: Shogaol-huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties.
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.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Pérez-Areales
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Ornella
authors.initials: O
authors.lastname: Di Pietro
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN(2)UB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Espargaró
authors.affiliation: Nutrition and Food Science Department, XaRTA, INSA, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain; CIBER CB06/03 Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Vallverdú-Queralt
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Ilaria M
authors.initials: IM
authors.lastname: Ragusa
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.affiliation: Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, LabEx LERMIT, 1, Avenue de la Terrasse, 91198 Gyf-sur-Yvette, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guillou
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain.
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN(2)UB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Raimon
authors.initials: R
authors.lastname: Sabaté
authors.affiliation: Nutrition and Food Science Department, XaRTA, INSA, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain; CIBER CB06/03 Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Lamuela-Raventós
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia (Campus Torribera), and IBUB, Universitat de Barcelona, Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain. Electronic address: dmunoztorrero@ub.edu.
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002396:Catechols; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D066329:Protein Aggregates; C404519:huprine Y; D016875:tau Proteins; C040115:shogaol; D000110:Acetylcholinesterase
keywords: Aβ aggregation inhibitors; Dual binding site AChE inhibitors; Multitarget compounds; Phenolic antioxidants; Tau aggregation inhibitors