Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites

Bianca K. Verlinden, Marna De Beer, Boobalan Pachaiyappan, Ethan Besaans, Warren A. Andayi, Janette Reader, Jandeli Niemand, Riette Van Biljon, Kiplin Guy, Timothy Egan, Patrick M. Woster, Lyn Marie Birkholtz

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish
Pages (from-to)5131-5143
Number of pages13
JournalBioorganic and Medicinal Chemistry
Issue number16
StatePublished - Aug 15 2015

Bibliographical note

Funding Information:
We thank Kathryn Wicht for assistance with the β-hematin inhibition assays at the University of Cape Town; Colin Dubick, Ethan Marrow, Youxuan Li for assistance with chemical synthesis at University of South Carolina and Gloria Holbrook and Fangyi Zhu for assistance with physicochemical properties at St Judes. This work was supported by the South African National Research Foundation ( FA2007050300003 & UID: 84627), the University of Pretoria and the South African Medical Research Council Strategic Health Initiatives Partnerships with the Medicines for Malaria Venture for funding. Any opinion, findings and conclusion exqpressed in this paper are those of the author(s) and therefore the NRF does not accept any liability in regard hereto.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.


  • (Bis)thiourea
  • (Bis)urea
  • Antimalarial drugs
  • Malaria
  • Plasmodium
  • Polyamine analogue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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