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

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

Journal:
Science (New York, N.Y.), Volume: 329, Issue: 5996
Published:
September 3, 2010
PMID:
20813948
Authors:
Matthias Rottmann M, Case McNamara C, Bryan K S Yeung BK, Marcus C S Lee MC, Bin Zou B, Bruce Russell B, Patrick Seitz P, David M Plouffe DM, Neekesh V Dharia NV, Jocelyn Tan J, Steven B Cohen SB, Kathryn R Spencer KR, Gonzalo E González-Páez GE, Suresh B Lakshminarayana SB, Anne Goh A, Rossarin Suwanarusk R, Timothy Jegla T, Esther K Schmitt EK, Hans-Peter Beck HP, Reto Brun R, Francois Nosten F, Laurent Renia L, Veronique Dartois V, Thomas H Keller TH, David A Fidock DA, Elizabeth A Winzeler EA, Thierry T Diagana TT
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.