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J Am Chem Soc. 2013 Jan 23;135(3):1037-47. doi: 10.1021/ja308741e. Epub 2013 Jan 9.

The single crystal X-ray structure of β-hematin DMSO solvate grown in the presence of chloroquine, a β-hematin growth-rate inhibitor.

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1
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.

Abstract

Single crystals of solvated β-hematin were grown from a DMSO solution containing the antimalarial drug chloroquine, a known inhibitor of β-hematin formation. In addition, a kinetics study employing biomimetic lipid-water emulsion conditions was undertaken to further investigate the effect of chloroquine and quinidine on the formation of β-hematin. Scanning electron microscopy shows that the external morphology of the β-hematin DMSO solvate crystals is almost indistinguishable from that of malaria pigment (hemozoin), and single crystal X-ray diffraction confirms the presence of μ-propionato coordination dimers of iron(III) protoporphyrin IX. The free propionic acid functional groups of adjacent dimers hydrogen bond to included DMSO molecules, rather than forming carboxylic acid dimers. The observed exponential kinetics were modeled using the Avrami equation, with an Avrami constant equal to 1. The decreased rate of β-hematin formation observed at low concentrations of both drugs could be accounted for by assuming a mechanism of drug adsorption to sites on the fastest growing face of β-hematin. This behavior was modeled using the Langmuir isotherm. Higher concentrations of drug resulted in decreased final yields of β-hematin, and an irreversible drug-induced precipitation of iron(III) protoporphyrin IX was postulated to account for this. The model permits determination of the equilibrium adsorption constant (K(ads)). The values for chloroquine (log K(ads) = 5.55 ± 0.03) and quinidine (log K(ads) = 4.92 ± 0.01) suggest that the approach may be useful as a relative probe of the mechanism of action of novel antimalarial compounds.

PMID:
23253048
PMCID:
PMC3553314
DOI:
10.1021/ja308741e
[Indexed for MEDLINE]
Free PMC Article
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