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)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 GSK3ß-dependent tau phosphorylation. In addition, molecules 9 and 4 effectively counteract Aß-aggregation on exposure to Aß1-40, as well as Aß1-40 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 Aß-aggregating and tau-phosphorylation inhibitory capacities, has been discovered for the potential treatment of AD.

Crystal structure of ethyl 2-chloro-6-methyl-quinoline-3-carboxyl-ate.

In the title compound, C13H12ClNO2, the dihedral angle between the planes of the quinoline ring system (r.m.s. deviation = 0.029 Å) and the ester group is 54.97 (6)°. The C-O-C-Cm (m = meth-yl) torsion angle is -140.62 (16)°. In the crystal, mol-ecules inter-act via aromatic π-π stacking [shortest centroid-centroid separation = 3.6774 (9) Å] generating (010) sheets.

Crystal structure of ethyl 2-chloro-5,8-di-meth-oxy-quinoline-3-carboxyl-ate.

In the title compound, C14H14ClNO4, the dihedral angle between the quinoline ring system (r.m.s. deviation = 0.0142 Å) and ester planes is 18.99 (3)°. The C-O-C-Cm (m = meth-yl) torsion angle is -172.08 (10)°, indicating a trans conformation. In the crystal, the mol-ecules are linked by C-H⋯O and C-H⋯N inter-actions, generating layers lying parallel to (101). Aromatic π-π stacking [centroid-centroid distances = 3.557 (2) and 3.703 (2)Å] links the layers into a three-dimensional network.

7-Meth-oxy-2-phenyl-quinoline-3-carbaldehyde.

In the title mol-ecule, C17H13NO2, the phenyl ring is inclined to the quinoline ring system by 43.53 (4)°. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming double-stranded chains propagating along [011]. These chains are linked via π-π inter-actions involving inversion-related quinoline rings; the shortest centroid-centroid distance is 3.6596 (17) Å.