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

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dc.contributor.author Verlinden, Bianca K.
dc.contributor.author De Beer, Marna
dc.contributor.author Pachaiyappan, Boobalan
dc.contributor.author Besaans, Ethan
dc.contributor.author Anday, Warren A.
dc.contributor.author Reader, Janette
dc.contributor.author Niemand, Jandeli
dc.contributor.author Van Biljon, Riette
dc.contributor.author Guy, Kiplin
dc.contributor.author Egan, Timothy
dc.contributor.author Woster, Patrick M.
dc.contributor.author Birkholtz, Lyn-Marie
dc.date.accessioned 2015-09-08T10:05:00Z
dc.date.available 2015-09-08T10:05:00Z
dc.date.issued 2015-08
dc.description.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. en_ZA
dc.description.embargo 2016-08-31 en_ZA
dc.description.librarian hb2015 en_ZA
dc.description.sponsorship 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. en_ZA
dc.description.uri http://www.elsevier.com/locate/bmc en_ZA
dc.identifier.citation Verlinden, BK, De Beer, M, Pachaiyappan, B, Besaans, E, Andayi, WA, Reader, J, Niemand, J, Van Biljon, R, Guy, K, Egan, T, Woster, PM & Birkholtz, L-M 2015, 'Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites', Bioorganic and Medicinal Chemistry, vol. 23, no. 16, pp. 5131-5143. en_ZA
dc.identifier.issn 0968-0896 (print)
dc.identifier.issn 1464-3391 (online)
dc.identifier.other 10.1016/j.bmc.2015.01.036
dc.identifier.uri http://hdl.handle.net/2263/49742
dc.language.iso en en_ZA
dc.publisher Elsevier en_ZA
dc.rights © 2015 Elsevier Ltd. All rights reserved. Notice : this is the author’s version of a work that was accepted for publication in Bioorganic and Medicinal Chemistry.Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic and Medicinal Chemistry, vol. 23, no.16, pp. 5131-5143, 2015. doi : 10.1016/j.bmc.2015.01.036. en_ZA
dc.subject Malaria en_ZA
dc.subject Plasmodium en_ZA
dc.subject Polyamine analogue en_ZA
dc.subject Antimalarial drugs en_ZA
dc.subject (Bis)urea en_ZA
dc.subject (Bis)thiourea en_ZA
dc.title Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites en_ZA
dc.type Postprint Article en_ZA


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