Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease

Eur J Med Chem. 2016 Aug 8:118:178-92. doi: 10.1016/j.ejmech.2016.04.023.

Nuria García-Font ¹, Hasna Hayour ², Ali Belfaitah ³, Jorge Pedraz ⁴, Ignacio Moraleda ⁵, Isabel Iriepa ⁵, Abdelmalek Bouraiou ², Mourad Chioua ⁶, José Marco-Contelles ⁷, María Jesús Oset-Gasque ⁸

Affiliations

1 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.
2 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.
3 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.
4 Department of Biochemistry and Molecular Biology II, School of Pharmacy, University Complutense Madrid (UCM), 28040 Madrid, Spain.
5 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.
6 Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
7 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.
8 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.

PMID: 27128182 DOI: 10.1016/j.ejmech.2016.04.023

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.

Keywords

Alzheimer's disease; Anticholinesterasics; Beta-amyloid aggregation; Neuroprotection; Tacrine; Tau-phosphorylation.

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