Spiroindolones, a potent compound class for the treatment of malaria.

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.

• Authors: Matthias Rottmann, Case McNamara, Bryan K S Yeung, Marcus C S Lee, Bin Zou, Bruce Russell, Patrick Seitz, David M Plouffe, Neekesh V Dharia, Jocelyn Tan, Steven B Cohen, Kathryn R Spencer, Gonzalo E González-Páez, Suresh B Lakshminarayana, Anne Goh, Rossarin Suwanarusk, Timothy Jegla, Esther K Schmitt, Hans-Peter Beck, Reto Brun, Francois Nosten, Laurent Renia, Veronique Dartois, Thomas H Keller, David A Fidock, Elizabeth A Winzeler, Thierry T Diagana
• Journal: Science (New York, N.Y.) (Science) Vol. 329 Issue 5996 Pg. 1175-80 (Sep 03 2010) ISSN: 1095-9203 [Electronic] United States
• PMID: 20813948 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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