Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.
The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.
Yeung
Bryan K S
BK
Novartis Institute for Tropical Diseases, 10 Biopolis Road, no. 05-01 Chromos, Singapore 138670. bryan.yeung@novartis.com
Zou
Bin
B
Rottmann
Matthias
M
Lakshminarayana
Suresh B
SB
Ang
Shi Hua
SH
Leong
Seh Yong
SY
Tan
Jocelyn
J
Wong
Josephine
J
Keller-Maerki
Sonja
S
Fischli
Christoph
C
Goh
Anne
A
Schmitt
Esther K
EK
Krastel
Philipp
P
Francotte
Eric
E
Kuhen
Kelli
K
Plouffe
David
D
Henson
Kerstin
K
Wagner
Trixie
T
Winzeler
Elizabeth A
EA
Petersen
Frank
F
Brun
Reto
R
Dartois
Veronique
V
Diagana
Thierry T
TT
Keller
Thomas H
TH
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010962:Plasmodium berghei; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C551616:5'-chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro(beta-carboline-1,3'-indol)-2'(1'H)-one; D000962:Antimalarials; D002243:Carbolines; D007211:Indoles; D013141:Spiro Compounds