Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues

Carla Martins, M. Carmo Carreiras, Rafael León, Cristóbal De Los Ríos, Manuela Bartolini, Vincenza Andrisano, Isabel Iriepa, Ignacio Moraleda, Enrique Gálvez, Manuela García, Javier Egea, Abdelouhaid Samadi, Mourad Chioua, José Marco-Contelles

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines 1-11 and pyrrolotacrine 13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC50 (eqBuChE) = 2.9 ± 0.4 μM; IC50 (hBuChE) = 119 ± 15 μM]. Conversely, pyrrolotacrines 12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b] quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC50 (EeAChE) = 0.61 ± 0.04 μM; IC50 (eqBuChE) = 0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer's disease.

Original languageEnglish
Pages (from-to)6119-6130
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number12
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

Keywords

  • AChE/BuChE inhibitors
  • Alzheimer's disease
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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