Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives

Daniel Silva, Mourad Chioua, Abdelouahid Samadi, M. Carmo Carreiras, María Luisa Jimeno, Eduarda Mendes, Cristóbal De Los Ríos, Alejandro Romero, Mercedes Villarroya, Manuela G. López, José Marco-Contelles

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48 Citations (Scopus)

Abstract

The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H- benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC 50 (EeAChE) = 0.069 ± 0.006 μM; IC 50 (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K i = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.

Original languageEnglish
Pages (from-to)4676-4681
Number of pages6
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number9
DOIs
Publication statusPublished - Sep 2011
Externally publishedYes

Keywords

  • AChE/BuChE inhibitors
  • Alzheimer's disease
  • Neuroprotection
  • Oxidative stress
  • Pyrazolotacrines

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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