Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum

Bioorg Med Chem. 2006 Jan 15;14(2):334-43. doi: 10.1016/j.bmc.2005.08.017. Epub 2005 Oct 10.

Abstract

A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC(50) values in the low nanomolar range.

MeSH terms

  • Aminacrine / chemical synthesis*
  • Aminacrine / pharmacology*
  • Animals
  • Antimalarials / pharmacology*
  • Cells, Cultured
  • Chloroquine / pharmacology*
  • Drug Resistance*
  • Erythrocytes / parasitology
  • Humans
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / growth & development

Substances

  • Antimalarials
  • Aminacrine
  • Chloroquine