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

被引:51
作者
Garcia-Font, Nuria [1 ,2 ]
Hayour, Hasna [3 ]
Belfaitah, Ali [3 ]
Pedraz, Jorge [1 ]
Moraleda, Ignacio [4 ]
Iriepa, Isabel [4 ]
Bouraiou, Abdelmalek [3 ]
Chioua, Mourad [5 ]
Marco-Contelles, Jose [2 ,5 ]
Jesus Oset-Gasque, Maria [1 ,2 ]
机构
[1] Univ Complutense Madrid, Sch Pharm, Dept Biochem & Mol Biol 2, E-28040 Madrid, Spain
[2] Univ Complutense Madrid, Univ Res Inst Neurochem IUIN, E-28040 Madrid, Spain
[3] Univ Freres Mentouri Constantine, Equipe Synth Mol Objectif Therapeut, Lab Prod Nat Origine Vegetale & Synth Organ PHYSY, Campus Chaabat Ersas, Constantine 25000, Algeria
[4] Univ Alcala de Henares, Dept Organ Chem & Inorgan Chem, Sch Biol Enviromental Sci & Chem, Ctra Barcelona,Km 33-5, Alcala De Henares 28817, Spain
[5] CSIC, IQOG, Med Chem Lab, C Juan Cierva 3, Madrid 28006, Spain
关键词
Tacrine; Alzheimer's disease; Anticholinesterasics; Neuroprotection; Beta-amyloid aggregation; Tau-phosphorylation; TACRINE-TROLOX HYBRIDS; ACETYLCHOLINESTERASE INHIBITORS; TRANSGENIC MICE; ANTIOXIDANT; DERIVATIVES; CHOLINESTERASE; QUINOLINE; PEPTIDES; ANALOGS; CELLS;
D O I
10.1016/j.ejmech.2016.04.023
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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)ethanone (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 mu m) and 4 (IC50 = 0.48 +/- 0.05 mu M) are potent, mixed-type (9: Ki = 0.0142 +/- 0.003 mu M), 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 mu M concentrations upon decreased viability of SHSY5Y cells induced by oxidative stress, and stimulators of GSK3 beta-dependent tau phosphorylation. In addition, molecules 9 and 4 effectively counteract A beta_aggregation on exposure to A beta(1-40), as well as A beta(1-40) 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 A beta-aggregating and tau-phosphorylation inhibitory capacities, has been discovered for the potential treatment of AD. (C) 2016 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:178 / 192
页数:15
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