The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials.
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de Villiers KA, Marques HM, Egan TJ
The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials.
J Inorg Biochem. 2008 Aug;102(8):1660-7. doi: 10.1016/j.jinorgbio.2008.04.001. Epub 2008 Apr 20.
- PubMed ID
- 18508124 [ View in PubMed]
- Abstract
The crystal structure of the complex formed between the antimalarial drug halofantrine and ferriprotoporphyrin IX (Fe(III)PPIX) has been determined by single crystal X-ray diffraction. The structure shows that halofantrine coordinates to the Fe(III) center through its alcohol functionality in addition to pi-stacking of the phenanthrene ring over the porphyrin. The length of the Fe(III)-O bond is consistent with an alkoxide and not an alcohol coordinating group. The iron porphyrin is five coordinate and monomeric. Changes in the electronic spectrum of Fe(III)PPIX upon addition of halofantrine base in acetonitrile solution are almost identical to those observed upon addition of quinidine free base in the same solvent. This suggests homologous binding. Molecular mechanics modeling of Fe(III)PPIX complexes of quinidine, quinine, 9-epiquinine and 9-epiquinidine based on this homology suggests that the antimalarially active quinidine and quinine can readily adopt conformations that permit formation of an intramolecular salt bridge between the protonated quinuclidine tertiary amino group and unprotonated heme propionate group, while the inactive epimers 9-epiquinidine and 9-epiquinine have to adopt high energy conformations in order to accommodate such salt bridge formation. We propose that salt bridge formation may interrupt formation of the hemozoin precursor dimer formed during the heme detoxification pathway and so account for the strong activity of the two active isomers.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Amodiaquine Fe(II)-protoporphyrin IX Small molecule Plasmodium falciparum YesBinderDetails Halofantrine Fe(II)-protoporphyrin IX Small molecule Plasmodium falciparum YesAntagonistDetails