The success of ferrochloroquine has encouraged the incorporation of the metallocene into many other anti-malarial agents. Unfortunately, the results have not always been favourable. The ferrocenic mefloquine and quinine analogues (for example, 31) were less active than the parent compounds,41 but this may be due to the instability of the ferrocenyl analogues in solution. Various ferrocenic analogues of artemisinin have been synthesized.42 It was proposed that Fe2+ in ferrocene may hasten the cleavage of the peroxide bond which is widely held to contribute to anti-plasmodial activity. Only one analogue (32) was found to be comparable to artemisinin. Coincidentally, 32 is also the only analogue with a basic amino function. The amino function enhances solubility through salt formation and this factor may be the reason why anti-plasmodial activity is retained.
In another investigation, ferrocenyl analogues of chalcones were found to exhibit micromolar inhibitory activity against chloroquine-resistant P. falciparum K1.43 The ferrocene ring was inserted into either ring A or ring B of the chalcone template. In general, better activity was observed when ring B was ferrocene. Compared to the chalcones where both rings A and B are phenyl, the ferrocenyl chalcones are generally less active. The most active members, 33 and 34, inhibited hypoxanthine uptake into P. falciparum K1 schizonticides with IC50 values of 4.5 mM and 5.1 mM, respectively. Differences in activity are not readily explained by the size or lipophilicity of the ferrocenyl chalcones.
Itoh and coworkers reported the anti-plasmodial activity of ferrocene ellagi-tannins which contain biphenic acid and ferrocene rings on the glucose core.44 Omission of ferrocene resulted in less active compounds.
Haworth and Hanlon designed a series of benzimidazolium salts with N-ferrocenylmethyl substituents.45 The authors noted that malaria increases the oxidative stress in red blood cells. In response to this situation, various
4-Nitrophenyl physiological processes in the infected host are stepped up, in particular those that supply substrates for reduction which would react with the reactive oxygen species generated by the parasite's presence in the body. They reasoned that exogenous compounds that are reductive targets would also be taken up by infected cells and manifest anti-plasmodial activity. In this context, methylene blue, a cationic redox dye, may exert its anti-plasmodial activity in this way. Since benzimidazolium salts like 35 have a similar reversible redox property, activity might be anticipated in these compounds. The inclusion of the ferrocene ring may be prompted by the fact that the metal ion also participates in a redox reaction (Fe2+/Fe3+ equilibrium) and may complement the redox property of the benzimidazolium moiety.
The outstanding anti-tumour activity of cisplatin has stimulated a search for other inorganic cytostatics.46 In the case of iron, attention has focused on ferrocene and ferricenium salts. The current status of these two classes of compounds as cytotoxic agents is reviewed in the following paragraphs. Derivatives in which an alkylating residue is attached to ferrocene (as in the case of ferrocenealdehyde N-methyl-N-^-chloroethyl hydrazone47) are excluded from this discussion.
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