Spiroindolones, a potent compound class for the treatment of malaria

Science. 2010 Sep 3;329(5996):1175-80. doi: 10.1126/science.1193225.

Abstract

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Antimalarials / administration & dosage
  • Antimalarials / chemistry
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Cell Line
  • Drug Discovery
  • Drug Resistance
  • Erythrocytes / parasitology
  • Female
  • Genes, Protozoan
  • Humans
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Male
  • Mice
  • Models, Molecular
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Mutation
  • Parasitic Sensitivity Tests
  • Plasmodium berghei / drug effects*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / growth & development
  • Plasmodium vivax / drug effects*
  • Plasmodium vivax / growth & development
  • Protein Synthesis Inhibitors / administration & dosage
  • Protein Synthesis Inhibitors / chemistry
  • Protein Synthesis Inhibitors / pharmacokinetics
  • Protein Synthesis Inhibitors / pharmacology
  • Protozoan Proteins / biosynthesis
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Rats
  • Rats, Wistar
  • Spiro Compounds / administration & dosage
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology*

Substances

  • Antimalarials
  • Indoles
  • Mutant Proteins
  • NITD 609
  • Protein Synthesis Inhibitors
  • Protozoan Proteins
  • Spiro Compounds
  • Adenosine Triphosphatases