Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.

Abstract

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.

• Authors: 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 Petersen, Reto Brun, Veronique Dartois, Thierry T Diagana, Thomas H Keller
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 14 Pg. 5155-64 (Jul 22 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20568778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5'-chloro-6,7-difluoro-3-methyl-2,3,4,9-tetrahydrospiro(beta-carboline-1,3'-indol)-2'(1'H)-one
• Antimalarials
• Carbolines
• Indoles
• Spiro Compounds

Topics

• Animals
• Antimalarials (chemical synthesis, pharmacokinetics, pharmacology)
• Carbolines (chemical synthesis, pharmacokinetics, pharmacology)
• Cell Line
• Crystallography, X-Ray
• Humans
• In Vitro Techniques
• Indoles (chemical synthesis, pharmacokinetics, pharmacology)
• Malaria (drug therapy)
• Mice
• Microsomes, Liver (metabolism)
• Molecular Structure
• Plasmodium berghei
• Spiro Compounds (chemical synthesis, pharmacokinetics, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship