期刊
MEDICINAL CHEMISTRY
卷 15, 期 1, 页码 51-58出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1573406414666180525132204
关键词
Malaria; Plasmodium; thiosemicarbazone; metal coordination; iron; copper; reactive oxygen
资金
- Australian Postgraduate Award
- South African Medical Research Council [MRC-RFA-UFSP-01-2013]
- CSU Pharmacy Foundation
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 MRCS human lung fibroblast line. 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.
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