Differential speciation of ferriprotoporphyrin IX in the presence of free base and diprotic 4-aminoquinoline antimalarial drugs

Abstract

The crystal structures of the μ-propionato dimer and π–π dimer of ferriprotoporphyrin IX (Fe(III)PPIX) have been determined by single crystal X-ray diffraction (SCD). Both species were obtained in the presence of the synthetic 4-aminoquinoline antimalarial drug, amodiaquine (AQ). The solution that afforded the μ-propionato dimer contained AQ as a free base (i.e. with both quinoline and terminal amine nitrogen atoms neutral). On the other hand, when the diprotic salt of AQ was included in the crystallization medium, the Fe(III)PPIX π–π dimer was obtained. The structure of the μ-propionato dimer, which is the discrete structural unit that constitutes haemozoin (malaria pigment), is identical to that obtained previously in presence of chloroquine free base. We suspect that the drug, via its two available basic sites, facilitates dissociation of one of the two Fe(III)PPIX propionic acid groups to yield a propionate group that is required for reciprocal coordination of the metal centre to form the centrosymmetric dimer. On the other hand, this proton transfer is not possible when the drug is present as a diprotic salt. In this case, the π–π dimer of Fe(III)PPIX is obtained. In the current study, the π–π dimer of haemin (chloro-Fe(III)PPIX) was obtained as a DMF solvate from non-aqueous aprotic solution (dimethyl formamide and chloroform), however the π–π dimer is also known to exist in aqueous solution (as aqua- or hydroxo-Fe(III)PPIX), where it is purportedly involved in the nucleation of haemozoin. We have been able to unambiguously determine the positions of all non-hydrogen atoms, as well as locate or assign all hydrogen atoms in the structure of the π–π dimer, which was not possible in the SCD structure of haemin reported by Koenig in 1965 owing to disorder in the vinyl and methyl substituents. Interestingly, no disorder in the methyl and vinyl groups is observed in the current structure. Both the π–π and μ-propionato dimers of Fe(III)PPIX are important species in the haem detoxification pathway in the malaria parasite and other blood-feeding organisms, and the structural insight gained in this study may assist target-driven design of new chemotherapeutic agents.