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Spiroindolones, a Potent Compound Class for the Treatment of Malaria
Ist Teil von
Science (American Association for the Advancement of Science), 2010-09, Vol.329 (5996), p.1175-1180
Ort / Verlag
Washington, DC: American Association for the Advancement of Science
Erscheinungsjahr
2010
Quelle
American Association for the Advancement of Science
Beschreibungen/Notizen
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.