A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum

J Med Chem. 2006 Sep 7;49(18):5623-5. doi: 10.1021/jm060399n.

Abstract

A class of hybrid molecules which we term 'reversed chloroquines' (RCQs) was designed, and a prototype molecule, N'-(7-chloroquinolin-4-yl)-N-[3-(10,11-dihydrodibenzo[b,f]azepin-5-yl)propyl]-N-methylpropane-1,3-diamine (1), was synthesized and tested against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. An in vitro assay against the two strains indicated that 1 was effective at low-nM concentrations against both strains. A preliminary study in mice demonstrated oral efficacy against P. chabaudi and the absence of obvious toxicity. The RCQ approach therefore appears to be feasible.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Chloroquine / analogs & derivatives*
  • Chloroquine / chemical synthesis
  • Chloroquine / chemistry
  • Chloroquine / pharmacology*
  • Dibenzazepines / chemical synthesis*
  • Dibenzazepines / chemistry
  • Dibenzazepines / pharmacology
  • Drug Resistance*
  • Female
  • Malaria / drug therapy
  • Malaria / parasitology
  • Mice
  • Plasmodium chabaudi
  • Plasmodium falciparum / drug effects*

Substances

  • Antimalarials
  • Dibenzazepines
  • N'-(7-chloroquinolin-4-yl)-N-(3-(10,11-dihydrodibenzo(b,f)azepin-5-yl)propyl)-N-methylpropane-1,3-diamine
  • Chloroquine