Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria

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, Esther K. Schmitt, Philipp Krastel, Eric Francotte, Kelli Kuhen, David Plouffe, Kerstin Henson, Trixie Wagner, Elizabeth A. Winzeler, Frank PetersenReto Brun, Veronique Dartois, Thierry T. Diagana, Thomas H. Keller

Research output: Contribution to journalArticlepeer-review

344 Scopus citations

Abstract

The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC50 of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC50 = 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.

Original languageEnglish (US)
Pages (from-to)5155-5164
Number of pages10
JournalJournal of medicinal chemistry
Volume53
Issue number14
DOIs
StatePublished - Jul 22 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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