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

Yeung, B. K. and Zou, B. and Rottmann, M. and Lakshminarayana, S. B. and Ang, S. H. and Leong, S. Y. and Tan, J. and Wong, J. and Keller-Maerki S., and Fischli, C. and Goh, A. and Schmitt, E. K. and Krastel, P. and Francotte, E. and Kuhen, K. and Plouffe, D. and Henson, K. and Wagner, T. and Winzeler, E. A. and Petersen, F. and Brun, R. and Dartois, V. and Diagana, T. T. and Keller, T. H.. (2010) Spirotetrahydro beta-carbolines (spiroindolones) : a new class of potent and orally efficacious compounds for the treatment of malaria. Journal of Medicinal Chemistry, 53 (14). pp. 5155-5164.

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Official URL: http://edoc.unibas.ch/dok/A5843026

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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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Sep 2018 14:24
Deposited On:08 Jun 2012 06:47

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