Spiroindolones, a Potent Compound Class for the Treatment of Malaria

• DOI: 10.1126/science.1193225
• Publication Date: 2010-09-02T19:25:55Z
• 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. Gonzál...; Suresh B. Lakshmi...; 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. Winz...; Thierry T. Diagana
• Keywords: Nonsynonymous substitution

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