Spiroindolones, a new and potent chemotype for the treatment of malaria

By M. Rottmann, C. McNamara, B. Yeung, Marcus C. S. Lee, B. Zou, B. Russell, P. Seitz, David M. Plouffe, N. Dharia, J. Tan and 17 more. Science, 2010

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Antimalarial Drug Candidate Spiroindolones were discovered as promising antimalarial drug candidates through a high-throughput screening approach that should be applicable to a range of neglected infectious diseases. Rottmann et al. (p. 1175; see the Perspective by Wells) present the preclinical profile for an optimized spiroindolone drug candidate, NITD609. They obtained evidence for a decrease in drug sensitivity in strains of the malaria parasite Plasmodium falciparum bearing amino acid mutations in the P-type ATPase, indicating possible mechanisms of action and/or resistance. High-throughput screening has offered up an oral antimalarial drug and pointers to its mechanism of action. 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.

Subfields: Infectious Diseases, Oncology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/ad33693f5e33b188a01e892767a31b08c59ae10f

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