Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation

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dc.contributor.advisorEgan, Timothy Jen_ZA
dc.contributor.authorNcokazi, Kanyile Ken_ZA
dc.date.accessioned2014-08-13T14:28:48Z
dc.date.available2014-08-13T14:28:48Z
dc.date.issued2005en_ZA
dc.descriptionIncludes bibliographical references.en_ZA
dc.description.abstractThermodynamic compensation in the interaction of quinoline antimalarials with haematin in 40% (v/v) aqueous OMSO has been compared with that in pure aqueous solution. The data indicate that the degree of desolvation and loss of conformational freedom is identical in both systems. The nature of interactions between quinoline drugs and haematin was investigated spectroscopically in organic and mixed solvents. Free energies of association of chloroquine, quinine and quinidine with haematin are largely insensitive to the increasing concentration of NaCI0. This demonstrates that electrostatic interactions play a minor role in the overall stability of these complexes under these conditions. Increasing concentration of OM SO weakens association of chloroquine, amodiaquine, quinine, quinidine and 9-epiquinine with haematin. These effects suggest that the interactions are hydrophobic. Furthermore, it has been demonstrated that free energy of association with haematin weakens as a function of decreasing solvent polarity in organic solvents. However, free energies of association are weaker in mixed aqueous solvents than in pure organic solvents. This indicates that dispersion and electrostatic interactions are relatively stronger in a non-aqueous environment. A new assay has been developed for measuring inhibition of ,ß-haematin formation using 5% (v/v) aqueous pyridine solution. This pyridine solution forms a low complex with haematin in aqueous solution but not with ,ß-haematin. Formation of ß-haematin is brought about in 4.5 M acetate, pH 4.5 at 60°C. The assay is rapid (60 min incubation) and requires no centrifugation or expensive radioactive material. This assay is compatible with high throughput screening and analysis can be done by visual inspection of ,ß- haematin inhibitors. The IC⁵⁰ values obtained were compared with those reported in other assays for 13 compounds investigated. There was generally a good correlation between the pyridine assay and other assays. Used qualitatively, the method was also employed for screening 48 compounds for ,ß-haematin inhibition. All of these compounds produced results in agreement with expectation from previous investigations.en_ZA
dc.identifier.apacitationNcokazi, K. K. (2005). <i>Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/6350en_ZA
dc.identifier.chicagocitationNcokazi, Kanyile K. <i>"Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2005. http://hdl.handle.net/11427/6350en_ZA
dc.identifier.citationNcokazi, K. 2005. Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Ncokazi, Kanyile K AB - Thermodynamic compensation in the interaction of quinoline antimalarials with haematin in 40% (v/v) aqueous OMSO has been compared with that in pure aqueous solution. The data indicate that the degree of desolvation and loss of conformational freedom is identical in both systems. The nature of interactions between quinoline drugs and haematin was investigated spectroscopically in organic and mixed solvents. Free energies of association of chloroquine, quinine and quinidine with haematin are largely insensitive to the increasing concentration of NaCI0. This demonstrates that electrostatic interactions play a minor role in the overall stability of these complexes under these conditions. Increasing concentration of OM SO weakens association of chloroquine, amodiaquine, quinine, quinidine and 9-epiquinine with haematin. These effects suggest that the interactions are hydrophobic. Furthermore, it has been demonstrated that free energy of association with haematin weakens as a function of decreasing solvent polarity in organic solvents. However, free energies of association are weaker in mixed aqueous solvents than in pure organic solvents. This indicates that dispersion and electrostatic interactions are relatively stronger in a non-aqueous environment. A new assay has been developed for measuring inhibition of ,ß-haematin formation using 5% (v/v) aqueous pyridine solution. This pyridine solution forms a low complex with haematin in aqueous solution but not with ,ß-haematin. Formation of ß-haematin is brought about in 4.5 M acetate, pH 4.5 at 60°C. The assay is rapid (60 min incubation) and requires no centrifugation or expensive radioactive material. This assay is compatible with high throughput screening and analysis can be done by visual inspection of ,ß- haematin inhibitors. The IC⁵⁰ values obtained were compared with those reported in other assays for 13 compounds investigated. There was generally a good correlation between the pyridine assay and other assays. Used qualitatively, the method was also employed for screening 48 compounds for ,ß-haematin inhibition. All of these compounds produced results in agreement with expectation from previous investigations. DA - 2005 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2005 T1 - Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation TI - Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation UR - http://hdl.handle.net/11427/6350 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/6350
dc.identifier.vancouvercitationNcokazi KK. Interactions of quinoline antimalarials with haematin and their effect on ß-haematin formation. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2005 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/6350en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.titleInteractions of quinoline antimalarials with haematin and their effect on ß-haematin formationen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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