Spiroindolones, a potent compound class for the treatment of malaria.
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.
Rottmann
Matthias
M
Swiss Tropical and Public Health Institute, Parasite Chemotherapy, CH-4002 Basel, Switzerland.
McNamara
Case
C
Yeung
Bryan K S
BK
Lee
Marcus C S
MC
Zou
Bin
B
Russell
Bruce
B
Seitz
Patrick
P
Plouffe
David M
DM
Dharia
Neekesh V
NV
Tan
Jocelyn
J
Cohen
Steven B
SB
Spencer
Kathryn R
KR
González-Páez
Gonzalo E
GE
Lakshminarayana
Suresh B
SB
Goh
Anne
A
Suwanarusk
Rossarin
R
Jegla
Timothy
T
Schmitt
Esther K
EK
Beck
Hans-Peter
HP
Brun
Reto
R
Nosten
Francois
F
Renia
Laurent
L
Dartois
Veronique
V
Keller
Thomas H
TH
Fidock
David A
DA
Winzeler
Elizabeth A
EA
Diagana
Thierry T
TT
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*
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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