title: Design, synthesis and evaluation of 3-methylene-substituted indolinones as antimalarials.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, Research Institute for Medicines and Pharmaceutical Sciences, University of Lisbon, Av Prof Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Praveen Kumar
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Santos
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D007211:Indoles; D003546:Cysteine Endopeptidases; C416224:falcipain 2