Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against Plasmodium falciparum.
Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe(III)PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity, and cellular mechanisms for this compound class, but no comparably detailed investigations exist for other hemozoin inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring and capable of adopting flat conformations, optimal for π-π interactions with Fe(III)PPIX, inhibited β-hematin formation. The two most potent analogues showed nanomolar parasite activity, with little CQ cross-resistance, low cytotoxicity, and high in vitro microsomal stability. Selected analogues inhibited hemozoin formation in Plasmodium falciparum causing high levels of free heme. In contrast to quinolines, introduction of amine side chains did not lead to benzamide accumulation in the parasite. These data reveal complex relationships between heme binding, free heme levels, cellular accumulation, and in vitro activity of potential novel antimalarials.
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
Kathryn J
KJ
Wicht
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.|Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Observatory 7925, South Africa.
Jill M
JM
Combrinck
Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Observatory 7925, South Africa.
Peter J
PJ
Smith
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
Roger
R
Hunter
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
Timothy J
TJ
Egan
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D001549:Benzamides; D006420:Hemeproteins; C020753:hemozoin