Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 3, Pages 927-933Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.01.008
Keywords
Indolin-2-ones; Falcipain inhibitor; Antiplasmodial activity; Malaria
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Funding
- Fundacao para a Ciencia e a Tecnologia (Portugal) [PTDC/SAU-FCF/098734/2008, REDE/1518/REM/2005]
- FLAD through the Luso-American Collaborative Response Awards
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-FCF/098734/2008] Funding Source: FCT
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The design, synthesis and evaluation of 3-methylene-substituted indolinones as falcipain inhibitors and antiplasmodial agents are described. These compounds react readily with thiols via an addition-elimination mechanism, indicating their potential as cysteine protease inhibitors. Several indolinones containing a Leu-i-amyl recognition moiety were found to be moderate inhibitors of the Plasmodium falciparum cysteine protease falcipain-2, but not of the related protease falcipain-3, and displayed antiplasmodial activity against the chloroquine-resistant P falciparum W2 strain in the low micromolar range. Coupling a 7-chloroquinoline moiety to the 3-methylene-substituted indolinone scaffold led to a significant improvement in antiplasmodial activity. (C) 2011 Elsevier Masson SAS. All rights reserved.
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