title: Synthesis and structure-activity-relationship studies of thiazolidinediones as antiplasmodial inhibitors of the Plasmodium falciparum cysteine protease falcipain-2.
abstract: Following a structure-based virtual screening, a series of 2,4 thiazolidinediones was synthesized in order to explore structure activity relationships for inhibition of the Plasmodium falciparum cysteine protease falcipain-2 (FP-2) and of whole cell antiparasitic activity. Most compounds exhibited low micromolar antiplasmodial activities against the P. falciparum drug resistant W2 strain. The most active compounds of the series were tested for in vitro microsomal metabolic stability and found to be susceptible to hepatic metabolism. Subsequent metabolite identification studies highlighted the metabolic hot spots. Molecular docking studies of a frontrunner inhibitor were carried out to determine the probable binding mode of this class of inhibitors in the active site of FP-2.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Rajni Kant
authors.initials: RK
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Grace
authors.initials: G
authors.lastname: Mugumbate
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Mathew
authors.initials: M
authors.lastname: Njoroge
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council, Drug Discovery and Development Unit, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
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*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D045162:Thiazolidinediones; D003546:Cysteine Endopeptidases; C416224:falcipain 2
keywords: Antiplasmodial agents; Falcipain-2; Thiazolidinone