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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.

Original publication

DOI

10.1126/science.1193225

Type

Journal article

Journal

Science

Publication Date

03/09/2010

Volume

329

Pages

1175 - 1180

Keywords

Adenosine Triphosphatases, Animals, Antimalarials, Cell Line, Drug Discovery, Drug Resistance, Erythrocytes, Female, Genes, Protozoan, Humans, Indoles, Malaria, Male, Mice, Models, Molecular, Mutant Proteins, Mutation, Parasitic Sensitivity Tests, Plasmodium berghei, Plasmodium falciparum, Plasmodium vivax, Protein Synthesis Inhibitors, Protozoan Proteins, Rats, Rats, Wistar, Spiro Compounds