Background: The emergence of resistance to the artemisinins which are the current
mainstays for antimalarial chemotheraphy has created an environment where the development of
new drugs acting in a mechanistally discrete manner is a priority.
Objective: The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential
Methods: Fifteen compounds were generated using two condensation protocols and evaluated in
vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment
of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast
Results: The activity of the bis-thiosemicarbazones was highly dependent on the nature of the
arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive
compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent
antimalarial activity (4 compounds showing IC50 < 250 nM).
Conclusion: Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial
activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this
activity. Ongoing studies are aimed at further development of this series as potential antimalarials.