Thesis Abstract

On the premise that the resistance of malaria is related to the structure of the sickle haemoglobin molecule, a comparative denaturation of haemoglobin A (HbA), haemoglobin AS (HbAS) and haemoglobin S (HbS) in their relaxed states using sodium dodecyl sulphate (SDS) was carried out at pH 5.0 and 7.2 in the presence of two antimalarial drugs artemether and lumefantrine in both singly and in combination forms and monitored by UV-Visible spectrophotometer in the range of 250 nm-700 nm. The results were analysed by convolution of the obtained absorption spectra. Artemether and lumefantrine have similar effects on all haemoglobins but lumefantrine show more pronounced effects when compared to artemether at pH 5.0. Both antimalarial drugs converted haemoglobin from the R-state to predominantly the deoxy structure as well as increasing the aromaticity and unfolding of haemoglobin. The effects of artemether and lumefantrine were more destabilizing for HbS when compared to HbA and HbAS. The concentration-dependent decrease of the Soret band was observed, a condition that is achieved as a consequence of heme alkylation and subsequent disruption of the p electron delocalized system. Also, artemether and lumefantrine in combination led to the progressive, slow decay and to eventual loss of the Soret band, as a consequence of direct alkylation of the porphyrin ring and of its subsequent degradation. The decay in the Soret band was highest in HbS when compared to other haemoglobins; suggesting it has a higher drug response which agrees with the apparent resistance of sickle cell carriers to malaria. HbS showed the lowest decrease in Soret band when compared the HbA. The difference spectrra of all haemoglobins in the presence of SDS, pH 5.0 showed concentration-dependent positive peak at 275 nm and positive trough at 415 nm. The peak absorbance of the difference spectra at 275 nm suggest that the protein is unfolding and the unfolding predisposes the aromatic amino acid group to solvent in its environment and this causes the protein to expand while the positive trough at 415mm suggest exposure of the haem moiety of the studied proteins. Lumefantrine interracts more with haemoglobin when compared to arthemeter. This may suggest why arthemeter has high rapid onset but short term cure rate while lumefantrine has a long term cure rate with short treatment course. Artemether and lumefantrine combination shows a synergistic effect on reaction with haemoglobin and is effective in malaria treatment but cannot be used in prevention due to the generation of free radicals.

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