Spiroindolones, a potent compound class for the treatment of malaria

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 BrunFrancois Nosten, Laurent Renia, Veronique Dartois, Thomas H. Keller, David A. Fidock, Elizabeth A. Winzeler, Thierry T. Diagana

Research output: Contribution to journalArticle

771 Scopus citations

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-β-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.

Original languageEnglish (US)
Pages (from-to)1175-1180
Number of pages6
JournalScience
Volume329
Issue number5996
DOIs
StatePublished - Sep 3 2010

All Science Journal Classification (ASJC) codes

  • General

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    Rottmann, M., McNamara, C., Yeung, B. K. S., Lee, M. C. S., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., González-Páez, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H. P., ... Diagana, T. T. (2010). Spiroindolones, a potent compound class for the treatment of malaria. Science, 329(5996), 1175-1180. https://doi.org/10.1126/science.1193225