- Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: A key interaction observed in the solid-state and solution
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The quinoline methanol antimalarial drug mefloquine is a structural analogue of the Cinchona alkaloids, quinine and quinidine. We have elucidated the single crystal X-ray diffraction structure of the complexes formed between racemic erythro mefloquine and ferriprotoporphyrin IX (Fe(iii)PPIX) and show that alkoxide coordination is a key interaction in the solid-state. Mass spectrometry confirms the existence of coordination complexes of quinine, quinidine and mefloquine to Fe(iii)PPIX in acetonitrile. The length of the iron(iii)-O bond in the quinine and quinidine complexes as determined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy unequivocally confirms that coordination of the quinoline methanol compounds to Fe(iii)PPIX occurs in non-aqueous aprotic solution via their benzylic alkoxide functional group. UV-visible spectrophotometric titrations of the low-spin bis-pyridyl-Fe(iii)PPIX complex with each of the quinoline methanol compounds results in the displacement of a single pyridine molecule and subsequent formation of a six-coordinate pyridine-Fe(iii)PPIX-drug complex. We propose that formation of the drug-Fe(iii)PPIX coordination complexes is favoured in a non-aqueous environment, such as that found in lipid bodies or membranes in the malaria parasite, and that their existence may contribute to the mechanism of haemozoin inhibition or other toxicity effects that lead ultimately to parasite death. In either case, coordination is a key interaction to be considered in the design of novel antimalarial drug candidates.
- Gildenhuys, Johandie,Sammy, Chandre J.,Müller, Ronel,Streltsov, Victor A.,Le Roex, Tanya,Kuter, David,De Villiers, Katherine A.
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p. 16767 - 16777
(2015/10/06)
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- Synthesis and biological evaluation of 1,4-naphthoquinones and quinoline-5,8-diones as antimalarial and schistosomicidal agents
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Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The AgII-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO3 and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of β-hematin. The Royal Society of Chemistry 2012.
- Lanfranchi, Don Antoine,Cesar-Rodo, Elena,Bertrand, Beno?t,Huang, Hsin-Hung,Day, Latasha,Johann, Laure,Elhabiri, Mourad,Becker, Katja,Williams, David L.,Davioud-Charvet, Elisabeth
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experimental part
p. 6375 - 6387
(2012/09/05)
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