In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1209-13. doi: 10.1016/j.bmcl.2013.12.071. Epub 2014 Jan 9.

Abstract

In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI=12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.

Keywords: Chloroquinoline derivatives; Cytotoxicity; Lipinski’s rule; OSIRIS software; Trypanosoma cruzi.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemical synthesis
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology*
  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical*
  • Fibroblasts / drug effects
  • Mice
  • Molecular Structure
  • Phenotype
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*

Substances

  • Aminoquinolines
  • Trypanocidal Agents
  • 7-chloro-4-aminoquinoline