Abstract:
Out of all the tropical diseases, malaria presents a most serious health problem in the world causing an estimated 863,000 deaths in 2008. The majority of the deaths recorded for 2008 occurred in the African region mainly due to non-compliance to the World Health Organisation's guidelines for the treatment and prevention of the disease. WHO recommends artemisinin-based combination therapies (ACTs) as using combination therapy is expected to delay the development of parasite resistance to the drugs. Artemisinin resistant strains of the Plasmodium parasite have already emerged in the South-East Asian region. Because of the parasites ability to relatively rapidly develop resistance to the existing treatment, new drugs are needed to be used as either monotherapy or in combination with other drugs. The aim of this particular project was to synthesise a series of amino acid derived β- carboline alkaloids that have antimalarial properties. The accent has been put on synthesising chiral compounds from optically pure amino acid starting materials since previous research has identifed that stereochemistry at the C-10 carbon of β-carboline alkaloids is important for antimalarial activity. Another feature that was observed to be improving the antiplasmodial activity of this class of compounds, the presence of the dimethylated amino group attached to C-10, has also been incorporated into the targets of this thesis. The (10S) and (10R) stereoisomers of both 10-dimethylphenylalanine and 10- dimethylleucine-β-carboline alkaloids were successfully synthesised. An attempt to synthesise 10-dimethyllysine-β-carboline analogues was however not completed due to time constraints. Biological evaluation of (10S)-dimethylphenylalanine-β-carboline and its synthetic precursors, 1,2,3,4-tetrahydro-β-carboline intermediates, as well as the tetrahydro intermediates of the (R) stereoisomer established all analogues to be active in inhibiting the Plasmodium parasite. It was observed that the aromaticity of the β-carboline moiety is essential for improving both activity and selectivity of the compounds towards the parasite. Antimalarial activity for (10S)- dimethylphenylalanine-β-carboline was observed to be even better than the inhibitory activity of chloroquine making this compound a suitable candidate for in vivo testing.