oligomycins and Alzheimer-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 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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Drug Design; Electrophorus; Hep G2 Cells; Humans; Neuroprotective Agents; Oligomycins; Oxidative Stress; Peptide Fragments; Phosphorylation; Protein Aggregates; Rotenone; Tacrine; tau Proteins

Due to the complex nature of Alzheimer's disease, there is a renewed search for multipotent, nonhepatotoxic tacrines.. This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl-2,4,6,7,8,9-hexahydropyrazolo[4',3':5,6]pyrano[2,3-b]quinolin-5-amines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Aβ1-40 aggregation induced by acetylcholinesterase.. A new family of nonhepatotoxic showing selective acetylcholinesterase inhibition, permeable tacrine analogs have been discovered for the potential treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amyloid beta-Peptides; Cell Survival; Dose-Response Relationship, Drug; Hep G2 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Molecular Structure; Neurons; Neuroprotective Agents; Oligomycins; Peptide Fragments; Protein Aggregates; Pyrazoles; Rotenone; Structure-Activity Relationship

1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Calcium; Catalytic Domain; Cell Death; Cell Line, Tumor; Cholinesterase Inhibitors; Cytotoxins; Electron Transport Chain Complex Proteins; Electrophorus; Glucose; Hippocampus; Humans; Isomerism; Models, Molecular; Naphthyridines; Neuroprotective Agents; Okadaic Acid; Oligomycins; Oxygen; Peptide Fragments; Protein Binding; Protein Phosphatase 2; Rats; Rotenone; Structure-Activity Relationship