title: Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites.
abstract: A new series of potent potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized and evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone and terminal substituents increased the potency of analogues in the compound library 3-fold, with the most active compounds, 15 and 16, showing half-maximal inhibitory concentrations (IC50 values) of 28 and 30 nM, respectively, against various Plasmodium falciparum parasite strains without any cross-resistance. In vitro evaluation of the cytotoxicity of these analogues revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50 against the parasite). Preliminary biological evaluation of the polyamine analogue antiplasmodial phenotype revealed that (bis)urea compounds target parasite asexual proliferation, whereas (bis)thiourea compounds of the same series have the unique ability to block transmissible gametocyte forms of the parasite, indicating pluripharmacology against proliferative and non-proliferative forms of the parasite. In this manuscript, we describe these results and postulate a refined structure-activity relationship (SAR) model for antiplasmodial polyamine analogues. The terminally aryl/alkylated (bis)urea- and (bis)thiourea-polyamine analogues featuring a 3-5-3 or 3-6-3 carbon backbone represent a structurally novel and distinct class of potential antiplasmodials with activities in the low nanomolar range, and high selectivity against various lifecycle forms of P. falciparum parasites.
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Bianca K
authors: BK
authors: Verlinden
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Marna
authors: M
authors: de Beer
authors: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Boobalan
authors: B
authors: Pachaiyappan
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Ethan
authors: E
authors: Besaans
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Warren A
authors: WA
authors: Andayi
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Janette
authors: J
authors: Reader
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Jandeli
authors: J
authors: Niemand
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa.
authors: Riette
authors: R
authors: van Biljon
authors: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: Kiplin
authors: K
authors: Guy
authors: Department of Chemistry, University of Cape Town, Medical School, Observatory 7925, South Africa.
authors: Timothy
authors: T
authors: Egan
authors: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Patrick M
authors: PM
authors: Woster
authors: Department of Biochemistry, Faculty of Natural and Agricultural Sciences, Centre for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Pretoria 0028, South Africa. Electronic address: lbirkholtz@up.ac.za.
authors: Lyn-Marie
authors: LM
authors: Birkholtz
mesh_terms: D000478:Alkylation; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D011073:Polyamines; D014508:Urea; D013890:Thiourea
keywords: (Bis)thiourea; (Bis)urea; Antimalarial drugs; Malaria; Plasmodium; Polyamine analogue