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.
