Ferrocenic metal chelators : synthesis, biological and electrochemical studies
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University of Cape Town
Resistance of Plasmodium falciparum (P. falciparum) to well-established drugs throughout the world has necessitated urgent alternative treatment for malaria. Iron chelation therapy was considered as a possible approach since iron has been found crucial in the metabolic pathways of P. falciparum. A series of novel iron chelators were designed and synthesized based on thiosemicarbazone and/or ferrocenyl moieties. The novel compounds were characterized by NMR, infrared (IR) and mass spectroscopy as well as microanalysis and subjected to biological evaluation. All the N-substituted ferrocenic thiosemicarbazones were evaluated against a chloroquine resistant W2 strain of the malaria parasite P. falciparum and enzymes (falcipains 2 & 3) derived from the same parasite. The intermediate thiosemicarbazone thioesters were also tested against different malaria parasite including chloroquine resistant (K1) and chloroquine sensitive (307) strains as well as against the causative agent of African trypanosomiasis, Trypanosoma brucei (T. brucei). Of the intermediate thiosemicarbazone thioesters, compound 44y a bipyridyl compound was the most active against both K1 and 307 strains with ED50 values of 0.18 /lg/ml (0.625 /lM) and 0.021 /lg/ml (0.072 /lM), respectively. However, this compound 44y also showed similar toxicity to mammalian cells. A number of thiosemicarbazone thioesters displaying preferential potency against a chloroquine resistant (K1) strain were noted. For example, compounds 44a-h, 44k-m, 445, 44u-v were found to be more active against K1 than against the chloroquine sensitive (307) strain.
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Muganza, F. 2006. Ferrocenic metal chelators : synthesis, biological and electrochemical studies. University of Cape Town.