Quinoline antimalarials containing a dibemethin group are active against chloroquinone-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine-resistance transporter (PfCRT)

J Med Chem. 2011 Oct 13;54(19):6956-68. doi: 10.1021/jm2009698. Epub 2011 Sep 13.

Abstract

A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC(50) value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite's chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Biological Transport
  • CHO Cells
  • Cell Survival / drug effects
  • Chloroquine / pharmacology*
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Female
  • Malaria / drug therapy
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Molecular Structure
  • Oocytes / metabolism
  • Parasitemia / drug therapy
  • Parasitemia / parasitology
  • Parasitic Sensitivity Tests
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / metabolism
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / metabolism*
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • Antimalarials
  • Membrane Transport Proteins
  • PfCRT protein, Plasmodium falciparum
  • Protozoan Proteins
  • Chloroquine