Abstract:
The sustained control and elimination of malaria requires novel approaches to combat
the emergence of drug resistance. Plasmodium falciparum causes the most lethal form
of human malaria. Current therapeutics have shown decreased efficacy as a result of
P. falciparum developing resistance to them. Consequently, novel antimalarial agents
with new mechanisms of action are urgently needed to aid in the control and ultimate
eradication of this disease and should display low resistance indices and high
selectivity indices. Polyamines are involved in a variety of cellular functions including
cell differentiation and proliferation and have been shown to be essential to malaria
parasites in vitro. However, these analogues lacked drug-like properties, negating their
use in malaria disease models in vivo. The objective of this study was to develop novel
polyamine analogues based on a previous generation of compounds and to determine
their antiplasmodial activity in vitro. Consequently, a novel series of (bis)urea and
(bis)thiourea polyamine analogues were designed and synthesised with moderately
high yields and purity. In silico evaluation of drug-likeness of these compounds
indicated low oral bioavailability overall, although the predicted values were improved
over the parent series. The antiplasmodial activity of the novel analogues indicated
that halogenation generally decreases activity except for bromination, which did
improve in vitro activity. Cheminformatics analysis enabled in-depth analysis of the
structure-activity relationships (SAR) of this class of compounds, allowing structural
features to be identified that are important for activity. Complementing the SAR with
quantitative structure-activity relationships (QSAR) allowed the determination of a
descriptor that weakly correlates with the analogues’ activities. The structural
requirements for activity were found to be based on representations of the polyamine
analogues molecular structures by means of circular atom neighbourhood’s. This work
therefore contributed to the further development of the polyamine analogues as
potential antimalarial drugs.
