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

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.

Grantor dc:publisher.institution

Department of Chemistry

Year dc:date.issued

2005

Author dc:creator

• Ncokazi, Kanyile K

Advisor dc:contributor.advisor

• Egan, Timothy J

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/6350

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/6350