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

AuthorsGarcía-Font, N.; Hayour, H.; Belfaitah, A.; Pedraz, J.; Moraleda, I.; Iriepa, I.; Bouraiou, A.; Chioua, Mourad ; Marco-Contelles, José ; Oset-Gasque, M. J.
Beta-amyloid aggregation
Alzheimer's disease
Issue Date2016
CitationEuropean Journal of Medicinal Chemistry 118: 178-192 (2016)
AbstractHerein 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 (IC = 0.47 ± 0.13 μM) and 4 (IC = 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 Aβaggregation on exposure to Aβ, as well as Aβ aggregation-dependent tau-oligomerization and phosphorylation in 396Ser, 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2016.04.023
Identifiersdoi: 10.1016/j.ejmech.2016.04.023
issn: 0223-5234
e-issn: 1768-3254
Appears in Collections:(IQOG) Artículos
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