title: Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities.
abstract: A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of  Plasmodium falciparum  in vitro. All analogues showed growth inhibitory activity against P. falciparum at less than 3 μM, with the majority having effective IC(50) values in the 100-650 nM range. Analogues arrested parasitic growth within 24 h of exposure due to a block in nuclear division and therefore asexual development. Moreover, this effect appears to be cytotoxic and highly selective to malaria parasites (>7000-fold lower IC(50) against P. falciparum) and is not reversible by the exogenous addition of polyamines. With this first report of potent antimalarial activity of polyamine analogues containing 3-7-3 or 3-6-3 carbon backbones and substituted terminal urea- or thiourea moieties, we propose that these compounds represent a structurally novel class of antimalarial agents.
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, PO Box x20, Pretoria, 0028, South Africa.
authors: Bianca K
authors: BK
authors: Verlinden
authors: Jandeli
authors: J
authors: Niemand
authors: Janette
authors: J
authors: Snyman
authors: Shiv K
authors: SK
authors: Sharma
authors: Ross J
authors: RJ
authors: Beattie
authors: Patrick M
authors: PM
authors: Woster
authors: Lyn-Marie
authors: LM
authors: Birkholtz
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D016054:DNA, Protozoan / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan; D011073:Polyamines; D002738:Chloroquine; D014508:Urea; D013890:Thiourea