title: Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease.
abstract: Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized 2-chloroquinolin-3-yl substituted PyranoTacrines (PTs) as multipotent tacrine analogues for Alzheimer's disease (AD) therapy. Among these compounds, 1-(5-amino-4-(2-chloro-7-methoxyquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano [2,3-b]quinolin-3-yl)éthanone (9) and ethyl 5-amino-4-(2-chloroquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinoline-3-carboxylate (4) were found to be non-neurotoxic agents in human neuroblastoma SHSY5Y cells. Compounds 9 (IC50 = 0.47 ± 0.13 μM) and 4 (IC50 = 0.48 ± 0.05 μM) are potent, mixed-type (9: Ki = 0.0142 ± 0.003 μM), and selective EeAChE inhibitors, binding at the both catalytic and peripheral anionic site of the enzyme. Compounds 9 and 4 are neuroprotective agents at low μM concentrations upon decreased viability of SHSY5Y cells induced by oxidative stress, and stimulators of GSK3β-dependent tau phosphorylation. In addition, molecules 9 and 4 effectively counteract Aβ-aggregation on exposure to Aβ1-40, as well as Aβ1-40 aggregation-dependent tau-oligomerization and phosphorylation in (396)Ser, which could be ascribed to the anti-aggregating properties shown in vitro. Thus, a new family of tacrine analogues, whose potent AChEI activity is linked to both their Aβ-aggregating and tau-phosphorylation inhibitory capacities, has been discovered for the potential treatment of AD.
authors.affiliation: Department of Biochemistry and Molecular Biology II, School of Pharmacy, University Complutense Madrid (UCM), 28040 Madrid, Spain; University Research Institute of Neurochemistry (IUIN), University Complutense Madrid (UCM), 28040 Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: García-Font
authors.affiliation: Equipe de Synthèse de Molécules à Objectif Thérapeutique, Laboratoire des Produits Naturels d'Origine Végétale et de Synthèse Organique (PHYSYNOR), Université des frères Mentouri-Constantine, Campus de Chaabat-Ersas, Constantine 25000, Algeria.
authors.forename: Hasna
authors.initials: H
authors.lastname: Hayour
authors.affiliation: Equipe de Synthèse de Molécules à Objectif Thérapeutique, Laboratoire des Produits Naturels d'Origine Végétale et de Synthèse Organique (PHYSYNOR), Université des frères Mentouri-Constantine, Campus de Chaabat-Ersas, Constantine 25000, Algeria. Electronic address: abelbelfaitah@yahoo.fr.
authors.forename: Ali
authors.initials: A
authors.lastname: Belfaitah
authors.affiliation: Department of Biochemistry and Molecular Biology II, School of Pharmacy, University Complutense Madrid (UCM), 28040 Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Pedraz
authors.affiliation: Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Enviromental Sciences and Chemistry, University Alcalá, Ctra. Barcelona, Km. 33.5, 28817, Alcalá de Henares, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.affiliation: Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Enviromental Sciences and Chemistry, University Alcalá, Ctra. Barcelona, Km. 33.5, 28817, Alcalá de Henares, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.affiliation: Equipe de Synthèse de Molécules à Objectif Thérapeutique, Laboratoire des Produits Naturels d'Origine Végétale et de Synthèse Organique (PHYSYNOR), Université des frères Mentouri-Constantine, Campus de Chaabat-Ersas, Constantine 25000, Algeria.
authors.forename: Abdelmalek
authors.initials: A
authors.lastname: Bouraiou
authors.affiliation: Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.affiliation: University Research Institute of Neurochemistry (IUIN), University Complutense Madrid (UCM), 28040 Madrid, Spain; Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: iqoc21@iqog.csci.es.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Department of Biochemistry and Molecular Biology II, School of Pharmacy, University Complutense Madrid (UCM), 28040 Madrid, Spain; University Research Institute of Neurochemistry (IUIN), University Complutense Madrid (UCM), 28040 Madrid, Spain. Electronic address: mjoset@ucm.es.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Oset-Gasque
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004593:Electrophorus; D056945:Hep G2 Cells; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009840:Oligomycins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D012402:Rotenone / Q000633:toxicity; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D009840:Oligomycins; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D012402:Rotenone; C031004:oligomycin A; D013619:Tacrine
keywords: Alzheimer's disease; Anticholinesterasics; Beta-amyloid aggregation; Neuroprotection; Tacrine; Tau-phosphorylation