title: Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy.
abstract: Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50= 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.
authors.affiliation: Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B. P 802, 3000 Sfax, Tunisia.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Dgachi
authors.affiliation: Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques, EA 481, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, UFR SMP, 19, rue Ambroise Paré, F-25000 Besançon, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Sokolov
authors.affiliation: Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques, EA 481, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, UFR SMP, 19, rue Ambroise Paré, F-25000 Besançon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Luzet
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 Street, 30-688 Krakow, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Godyń
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 Street, 30-688 Krakow, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Panek
authors.affiliation: Laboratory of Cell Toxicology, EA 4267, Univ. Bourgogne Franche-Comté, 19 rue Ambroise Paré, F-25030 Besançon Cedex, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bonet
authors.affiliation: Laboratory of Cell Toxicology, EA 4267, Univ. Bourgogne Franche-Comté, 19 rue Ambroise Paré, F-25030 Besançon Cedex, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Martin
authors.affiliation: Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Enviromental Sciences and Chemistry, University Alcala, Ctra. Barcelona, Km. 33.6, 28871 Alcala de Henares, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.affiliation: Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Enviromental Sciences and Chemistry, University Alcala, Ctra. Barcelona, Km. 33.6, 28871 Alcala de Henares, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.affiliation: Department of Analytical Chemistry, Physical Chemistry, and Chemical Engineering, School of Biology, Enviromental Sciences and Chemistry, University Alcala, Ctra. Barcelona, Km. 33.6, 28871 Alcala de Henares, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Iriepa
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Czechia.
authors.forename: Jana
authors.initials: J
authors.lastname: Janockova
authors.affiliation: Laboratory of Cell Toxicology, EA 4267, Univ. Bourgogne Franche-Comté, 19 rue Ambroise Paré, F-25030 Besançon Cedex, France.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Czechia.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 Street, 30-688 Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B. P 802, 3000 Sfax, Tunisia. Electronic address: fakher.chabchoub@yahoo.fr.
authors.forename: Fakher
authors.initials: F
authors.lastname: Chabchoub
authors.affiliation: Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: iqoc21@iqog.csic.es.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques, EA 481, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, UFR SMP, 19, rue Ambroise Paré, F-25000 Besançon, France. Electronic address: lhassane.ismaili@univ-fcomte.fr.
authors.forename: Lhassane
authors.initials: L
authors.lastname: Ismaili
mesh_terms: D000110:Acetylcholinesterase; D000544:Alzheimer Disease / Q000188:drug therapy; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D006801:Humans
chemical_list: D000634:Aminoquinolines; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D058851:GPI-Linked Proteins; C548244:ACHE protein, human; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Antioxidants; Brain blood barrier; Hepatotoxicity; Molecular modeling; Multifunctional agents