title: Spiroindolones, a potent compound class for the treatment of malaria.
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-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.
authors.affiliation: Swiss Tropical and Public Health Institute, Parasite Chemotherapy, CH-4002 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Case
authors.initials: C
authors.lastname: McNamara
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.forename: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.forename: Patrick
authors.initials: P
authors.lastname: Seitz
authors.forename: David M
authors.initials: DM
authors.lastname: Plouffe
authors.forename: Neekesh V
authors.initials: NV
authors.lastname: Dharia
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Tan
authors.forename: Steven B
authors.initials: SB
authors.lastname: Cohen
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Spencer
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: González-Páez
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Rossarin
authors.initials: R
authors.lastname: Suwanarusk
authors.forename: Timothy
authors.initials: T
authors.lastname: Jegla
authors.forename: Esther K
authors.initials: EK
authors.lastname: Schmitt
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D017125:Genes, Protozoan; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D010966:Plasmodium vivax / Q000187:drug effects* / Q000254:growth & development; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015800:Protozoan Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D007211:Indoles; D050505:Mutant Proteins; C552304:NITD 609; D011500:Protein Synthesis Inhibitors; D015800:Protozoan Proteins; D013141:Spiro Compounds; D000251:Adenosine Triphosphatases
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