title: Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active againstPlasmodium falciparum.
abstract: In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active againstPlasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases ofP. falciparumintracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wicht
authors.affiliation: Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Observatory 7925, South Africa.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Combrinck
authors.affiliation: Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Roger
authors.initials: R
authors.lastname: Hunter
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
keywords: Antimalarial; Plasmodium falciparum; hemozoin; triarylimidazole