The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials.

 

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dc.contributor.author de Villiers, Katherine A
dc.contributor.author Marques, Helder
dc.contributor.author Egan, Timothy J
dc.date.accessioned 2016-07-20T13:37:22Z
dc.date.available 2016-07-20T13:37:22Z
dc.date.issued 2008
dc.identifier http://dx.doi.org/10.1016/j.jinorgbio.2008.04.001
dc.identifier.citation de Villiers, K. A., Marques, H. M., & Egan, T. J. (2008). The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. Journal of inorganic biochemistry, 102(8), 1660-1667. en_ZA
dc.identifier.issn 0162-0134 en_ZA
dc.identifier.uri http://hdl.handle.net/11427/20552
dc.identifier.uri http://www.sciencedirect.com/science/article/pii/S0162013408001141
dc.description.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 p-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. en_ZA
dc.language eng en_ZA
dc.publisher Elsevier en_ZA
dc.source Journal of Inorganic Biochemistry en_ZA
dc.source.uri http://www.journals.elsevier.com/journal-of-inorganic-biochemistry/
dc.subject.other Malaria
dc.subject.other Antimalarials
dc.subject.other Halofantrine
dc.subject.other Quinine
dc.subject.other Quinidine
dc.subject.other Heme
dc.subject.other Crystal structure
dc.title The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. en_ZA
dc.type Journal Article en_ZA
dc.date.updated 2016-07-20T13:36:10Z
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation de Villiers, K. A., Marques, H., & Egan, T. J. (2008). The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. <i>Journal of Inorganic Biochemistry</i>, http://hdl.handle.net/11427/20552 en_ZA
dc.identifier.chicagocitation de Villiers, Katherine A, Helder Marques, and Timothy J Egan "The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials." <i>Journal of Inorganic Biochemistry</i> (2008) http://hdl.handle.net/11427/20552 en_ZA
dc.identifier.vancouvercitation de Villiers KA, Marques H, Egan TJ. The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. Journal of Inorganic Biochemistry. 2008; http://hdl.handle.net/11427/20552. en_ZA
dc.identifier.ris TY - Journal Article AU - de Villiers, Katherine A AU - Marques, Helder AU - Egan, Timothy J AB - 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 p-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. DA - 2008 DB - OpenUCT DP - University of Cape Town J1 - Journal of Inorganic Biochemistry LK - https://open.uct.ac.za PB - University of Cape Town PY - 2008 SM - 0162-0134 T1 - The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials TI - The crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials UR - http://hdl.handle.net/11427/20552 ER - en_ZA


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