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

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.