Abstract
Plasmodium falciparum is the most lethal species of malaria, which is responsible for about 90% of the reported cases around the globe. While Chloroquine has been the most reliable and effective drug for the treatment of malaria, artemisinin is the most effective form of malaria treatment reported thus far. It is administered orally in double or triple combination dose therapy with the primary aim of preventing or delaying the development of a drug resistant Plasmodium species.
Recent reports suggest the emergence of the drug tolerant species on the current malaria drug, artemisinin. This poses a global health threat since artemisinin is the most effective and reliable malaria drug to date. These findings necessitate the continuation of the search for new antimalarial chemotypes with different modes of action and the speeding up of the development and biological evaluation of such compounds. Quinoline containing drugs such as chloroquine 1 invade and accumulate in the infected cell food vacuole which then disrupts the formation of hemozoins, a product of detoxification of heme. The presence of heme in an infected cell leads to cell malfunction and eventually cell death.
The chemotypes of choice in this study are thiochromans, due to their ability of being converted into numerous compounds through various transformations such as oxidation and rearrangement reactions. The derived thiochromans in this study are modified to have various lipophilic characteristics and different stereochemistry to enable the investigation of how such characteristics affect the antimalarial activity of thiochromans in general.
To achieve our objectives, galactose was converted to a desired starting material galactal 64. This was achieved by acetylation of galactal with acetic anhydride, followed by halogenation with bromine at the alpha carbon and a reduction of the bromide with zinc and copper sulphate. Galactal was treated in a similar fashion as the glucal in our previously reported study to afford the desired thiochroman 70 with a galactosyl epimer.
A series of novel carbohydrate fused thiochromans were synthesised in order to investigate the influence of alkyl substituents on the aromatic ring of the thiophenol moiety and protecting groups and stereochemistry on the sugar component of the target molecules.
To achieve this, benzene was converted into several thiophenols with different alkyl chains on C-4. Benzene was subjected to Friedel-Crafts acylation followed by reduction with zinc in water to afford...
M.Sc. (Chemistry)