Open AccessSpirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
Author(s) -
Bryan K. S. Yeung,
Bin Zou,
Matthias Rottmann,
Suresh B. Lakshminarayana,
Shi Hua Ang,
Seh Yong Leong,
Jocelyn Tan,
Josephine Wong,
Sonja Keller-Maerki,
Christoph Fischli,
Anne Goh,
E. Schmitt,
Philipp Krastel,
Eric Francotte,
Kelli Kuhen,
David Plouffe,
Kerstin Henson,
Trixie Wagner,
Elizabeth A. Winzeler,
Frank Petersen,
Reto Brun,
Véronique Dartois,
Thierry T. Diagana,
Thomas H. Keller
Publication year - 2010
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm100410f
Subject(s) - plasmodium berghei , chemistry , enantiomer , pharmacology , malaria , plasmodium falciparum , pharmacokinetics , in vitro , oral administration , stereochemistry , structure–activity relationship , biochemistry , immunology , medicine
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.