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Review
. 2008 Mar;3(3):383-91.
doi: 10.1002/cmdc.200700127.

Ferrocene conjugates of chloroquine and other antimalarials: the development of ferroquine, a new antimalarial

Daniel Dive  1 , Christophe Biot
Affiliations
Review

Ferrocene conjugates of chloroquine and other antimalarials: the development of ferroquine, a new antimalarial

Daniel Dive et al. ChemMedChem. 2008 Mar.

Abstract

A convenient approach to antimalarial drug discovery is the use of the organic scaffold of a known antimalarial drug and an organometallic moiety to alter its unwanted properties and/or to optimize its initial effects. This minireview focuses mainly on the discovery of ferroquine, which has emerged from a collaborative French discovery project, and efforts to understand its mechanism of action and resistance.

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Figures

Figure 1
Figure 1
Chemical structure of ferroquine, the new antimalarial. The intramolecular H‐bond is indicated with dashed lines.
Figure 2
Figure 2
The template, chloroquine 1, and the ferrocene conjugates 2–12. R is an alkyl or a ferrocenylmethyl group, n varying from 2 to 6.
Figure 3
Figure 3
Artemisinin 13, artemisitene 14, and the ferrocene conjugates 15–20.
Figure 4
Figure 4
Quinine 21, mefloquine 22 and their respective ferrocene analogues 23 and 24. R1 and R2 are alkyl groups.
Figure 5
Figure 5
Atovaquone 25 and its respective ferrocene analogues 26. R is an alkyl group.
Figure 6
Figure 6
Ferroquine enantiomers.
Figure 7
Figure 7
Proposed metabolic pathway of ferroquine in human hepatic models. Main metabolites are in the dashed line box.
Figure 8
Figure 8
Mean IC50 values of FQ measured on seven different laboratory P. falciparum clones (open circles), ,  and on seven sets of field isolates from Gabon, Senegal, and Cambodia (filled circles).–
Figure 9
Figure 9
Proposed structure–activity relationships for ferroquine.
Figure 10
Figure 10
Induction of resistance to FQ tested on P. yoelii NS. Delay for the parasite to achieve 2 % blood parasitaemia starting from a 107 parasites infection. PyCQ+: CQ pressure for four days followed by three days release. PyCQR: CQ pressure according to the method of 2 % parasitaemia. PyFQR: FQ pressure according to the method of 2 % parasitaemia. PyFQ−: release of FQ pressure. Dotted lines, assays done on lines after cryopreservation: only the strain obtained under FQ pressure showed a loss of its resistance to the drug after cryopreservation. ED50 and ED90 indicate the times when resistance to CQ, MF, and FQ were tested on the different strains.
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References

    1. World Health Organization. The World Health Report 2006, http://www.who.int/en.
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    1. For a full‐length review on bioorganometallic chemistry of ferrocene, see: van Staveren D. R., Metzler‐Nolte N., Chem. Rev. 2004, 104, 5931–5986. - PubMed

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