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Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria

[Image: see text] 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 IC(50) of 90 nM. Structure−activity relationships for the optimization of...

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Autores principales: Yeung, Bryan K. S., Zou, Bin, Rottmann, Matthias, Lakshminarayana, Suresh B., Ang, Shi Hua, Leong, Seh Yong, Tan, Jocelyn, Wong, Josephine, Keller-Maerki, Sonja, Fischli, Christoph, Goh, Anne, Schmitt, Esther K., Krastel, Philipp, Francotte, Eric, Kuhen, Kelli, Plouffe, David, Henson, Kerstin, Wagner, Trixie, Winzeler, Elizabeth A., Petersen, Frank, Brun, Reto, Dartois, Veronique, Diagana, Thierry T., Keller, Thomas H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2010
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996867/
https://www.ncbi.nlm.nih.gov/pubmed/20568778
http://dx.doi.org/10.1021/jm100410f
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author Yeung, Bryan K. S.
Zou, Bin
Rottmann, Matthias
Lakshminarayana, Suresh B.
Ang, Shi Hua
Leong, Seh Yong
Tan, Jocelyn
Wong, Josephine
Keller-Maerki, Sonja
Fischli, Christoph
Goh, Anne
Schmitt, Esther K.
Krastel, Philipp
Francotte, Eric
Kuhen, Kelli
Plouffe, David
Henson, Kerstin
Wagner, Trixie
Winzeler, Elizabeth A.
Petersen, Frank
Brun, Reto
Dartois, Veronique
Diagana, Thierry T.
Keller, Thomas H.
author_facet Yeung, Bryan K. S.
Zou, Bin
Rottmann, Matthias
Lakshminarayana, Suresh B.
Ang, Shi Hua
Leong, Seh Yong
Tan, Jocelyn
Wong, Josephine
Keller-Maerki, Sonja
Fischli, Christoph
Goh, Anne
Schmitt, Esther K.
Krastel, Philipp
Francotte, Eric
Kuhen, Kelli
Plouffe, David
Henson, Kerstin
Wagner, Trixie
Winzeler, Elizabeth A.
Petersen, Frank
Brun, Reto
Dartois, Veronique
Diagana, Thierry T.
Keller, Thomas H.
author_sort Yeung, Bryan K. S.
collection PubMed
description [Image: see text] 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 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.
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spelling pubmed-69968672020-02-04 Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria Yeung, Bryan K. S. Zou, Bin Rottmann, Matthias Lakshminarayana, Suresh B. Ang, Shi Hua Leong, Seh Yong Tan, Jocelyn Wong, Josephine Keller-Maerki, Sonja Fischli, Christoph Goh, Anne Schmitt, Esther K. Krastel, Philipp Francotte, Eric Kuhen, Kelli Plouffe, David Henson, Kerstin Wagner, Trixie Winzeler, Elizabeth A. Petersen, Frank Brun, Reto Dartois, Veronique Diagana, Thierry T. Keller, Thomas H. J Med Chem [Image: see text] 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 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. American Chemical Society 2010-06-22 2010-07-22 /pmc/articles/PMC6996867/ /pubmed/20568778 http://dx.doi.org/10.1021/jm100410f Text en Copyright © 2010 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Yeung, Bryan K. S.
Zou, Bin
Rottmann, Matthias
Lakshminarayana, Suresh B.
Ang, Shi Hua
Leong, Seh Yong
Tan, Jocelyn
Wong, Josephine
Keller-Maerki, Sonja
Fischli, Christoph
Goh, Anne
Schmitt, Esther K.
Krastel, Philipp
Francotte, Eric
Kuhen, Kelli
Plouffe, David
Henson, Kerstin
Wagner, Trixie
Winzeler, Elizabeth A.
Petersen, Frank
Brun, Reto
Dartois, Veronique
Diagana, Thierry T.
Keller, Thomas H.
Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
title Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
title_full Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
title_fullStr Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
title_full_unstemmed Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
title_short Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria
title_sort spirotetrahydro β-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996867/
https://www.ncbi.nlm.nih.gov/pubmed/20568778
http://dx.doi.org/10.1021/jm100410f
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