Fady N. Akladios, Scott D. Andrew, Samantha J. Boog, Carmen de Kock, Richard K. Haynes and Christopher J. Parkinson* Pages 51 - 58 ( 8 )
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 antimalarial agents.
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 line.
Results: The activity of the bis-thiosemicarbazones was highly dependent on the nature of the erene 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.
Malaria, Plasmodium, thiosemicarbazone, metal coordination, iron, copper, reactive oxygen.
School of Biomedical Sciences, Charles Sturt University. Orange, NSW 2800, School of Biomedical Sciences, Charles Sturt University. Orange, NSW 2800, School of Biomedical Sciences, Charles Sturt University. Orange, NSW 2800, Division of Clinical Pharmacology, University of Cape Town, Groote Schuur Hospital, Observatory 7925, Centre for Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2531, School of Biomedical Sciences, Charles Sturt University. Orange, NSW 2800