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

Cristóbal De Los Ríos, Javier Egea, José Marco-Contelles, Rafael León, Abdelouahid Samadi, Isabel Iriepa, Ignacio Moraleda, Enrique Gálvez, Antonio G. García, Manuela G. López, Mercedes Villarroya, Alejandro Romero

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79 Citations (Scopus)


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 β 1-42 peptide (Aβ1-42). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in t 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.

Original languageEnglish
Pages (from-to)5129-5143
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - Jul 22 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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