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 08; 118:178-92.EJ

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

García-Font N

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.

Hayour H

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.

Belfaitah A

Pedraz J

Department of Biochemistry and Molecular Biology II, School of Pharmacy, University Complutense Madrid (UCM), 28040 Madrid, Spain.

Moraleda I

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.

Iriepa I

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.

Bouraiou A

Chioua M

Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.

Marco-Contelles J

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.

Oset-Gasque MJ

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsCholinesterase InhibitorsDrug DesignElectrophorusHep G2 CellsHumansNeuroprotective AgentsOligomycinsOxidative StressPeptide FragmentsPhosphorylationProtein AggregatesRotenoneTacrinetau Proteins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27128182

Citation

García-Font, Nuria, et al. "Potent Anticholinesterasic and Neuroprotective Pyranotacrines as Inhibitors of Beta-amyloid Aggregation, Oxidative Stress and Tau-phosphorylation for Alzheimer's Disease." European Journal of Medicinal Chemistry, vol. 118, 2016, pp. 178-92.

García-Font N, Hayour H, Belfaitah A, et al. 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;118:178-92.

García-Font, N., Hayour, H., Belfaitah, A., Pedraz, J., Moraleda, I., Iriepa, I., Bouraiou, A., Chioua, M., Marco-Contelles, J., & Oset-Gasque, M. J. (2016). Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease. European Journal of Medicinal Chemistry, 118, 178-92. https://doi.org/10.1016/j.ejmech.2016.04.023

García-Font N, et al. 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. PubMed PMID: 27128182.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease. AU - García-Font,Nuria, AU - Hayour,Hasna, AU - Belfaitah,Ali, AU - Pedraz,Jorge, AU - Moraleda,Ignacio, AU - Iriepa,Isabel, AU - Bouraiou,Abdelmalek, AU - Chioua,Mourad, AU - Marco-Contelles,José, AU - Oset-Gasque,María Jesús, Y1 - 2016/04/11/ PY - 2016/01/08/received PY - 2016/04/06/revised PY - 2016/04/08/accepted PY - 2016/4/30/entrez PY - 2016/4/30/pubmed PY - 2017/2/9/medline KW - Alzheimer's disease KW - Anticholinesterasics KW - Beta-amyloid aggregation KW - Neuroprotection KW - Tacrine KW - Tau-phosphorylation SP - 178 EP - 92 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 118 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/27128182/Potent_anticholinesterasic_and_neuroprotective_pyranotacrines_as_inhibitors_of_beta_amyloid_aggregation_oxidative_stress_and_tau_phosphorylation_for_Alzheimer's_disease_ DB - PRIME DP - Unbound Medicine ER -

Tags

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 08; 118:178-92.EJ