Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives

J Med Chem. 2010 Jul 22;53(14):5129-43. doi: 10.1021/jm901902w.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Butyrylcholinesterase / chemistry
  • Calcium / metabolism
  • Catalytic Domain
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Cytotoxins / pharmacology
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors
  • Electrophorus
  • Glucose / deficiency
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Humans
  • Isomerism
  • Models, Molecular
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Okadaic Acid / pharmacology
  • Oligomycins / pharmacology
  • Oxygen / metabolism
  • Peptide Fragments / toxicity
  • Protein Binding
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Protein Phosphatase 2 / chemistry
  • Rats
  • Rotenone / pharmacology
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Cytotoxins
  • Electron Transport Chain Complex Proteins
  • Naphthyridines
  • Neuroprotective Agents
  • Oligomycins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo(b)(1,8)naphthyridine-3-carboxylate
  • Rotenone
  • oligomycin A
  • Okadaic Acid
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Protein Phosphatase 2
  • Glucose
  • Oxygen
  • Calcium