Reversal of chloroquine resistance in Plasmodium falciparum by 9H-xanthene derivatives

Int J Antimicrob Agents. 2005 Aug;26(2):170-5. doi: 10.1016/j.ijantimicag.2005.04.018.

Abstract

Four new chemosensitisers against chloroquine-resistant Plasmodium falciparum based on the 9H-xanthene tricyclic scaffold were designed and synthesised in an attempt to identify simplified compounds that are easily accessible from commercially available starting materials. The compounds contain a common hydrophobic tricyclic 9H-xanthene moiety and an alkyl side chain with two amino groups, one of which is a tertiary substituted terminal amine, separated by three carbons and differing only in the chemical nature of the intermediary nitrogen atom. The best chemosensitising compound has a secondary amino group, showed a response modification index of 0.36 and caused a four-fold increase in chloroquine accumulation in a resistant strain of P. falciparum as well as having the highest selective therapeutic index when tested against a mammalian cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / pharmacology
  • CHO Cells
  • Chloroquine / pharmacokinetics*
  • Chloroquine / pharmacology*
  • Chloroquine / toxicity*
  • Cricetinae
  • Drug Interactions
  • Drug Resistance / drug effects*
  • Parasitic Sensitivity Tests* / methods
  • Plasmodium falciparum / drug effects*
  • Xanthenes / chemistry*
  • Xanthenes / pharmacology

Substances

  • Antimalarials
  • Xanthenes
  • Chloroquine