Biocatalytic synthesis of novel oxidized aromatic compounds as potential anti-bacterial and anti-cancer agents

A dissertation submitted In fulfilment of the degree Doctor of Philosophy (Chemistry) In the Faculty of Science School of Chemistry University of the Witwatersrand. Johannesburg 2015.According to the World Health Organization (WHO), cancer is a leading cause of death worldwide and has accounted for 7.6 million deaths (13% of all deaths) in 2008. The number of effective drugs available has been reduced by chemo resistant malignant tumors. Similarly, bacterial infections are one of the world’s most pressing public health problem. The major challenge in anti-bacterial treatment is due to the development of bacteria strains that are resistant to antibiotics. Each year more than 11 million people die from major infections such as MDR tuberculosis. In 2013, 9 million people fell ill with TB and 1.5 million died from the disease (WHO). Therefore there is a need for novel therapeutic alternatives such as the discovery of new anti-cancer and anti-bacterial agents. Benzofurans have attracted much attention due to their broad spectrum of pharmacological activities such as anti-cancer and anti-bacterial activities and one classical example is usnic acid. Most of the published synthesis of the benzofuran moiety involved the formation of annellated furan ring by intramolecular cyclisation of benzene, and these procedures involved a multi-step, rigorous reaction conditions and expensive catalyst. This research investigated the novel synthesis of benzofurans through the application of biocatalysis, where the reactions involved the use of the oxidative enzyme laccase to generate carbon-carbon bonds, carbon-oxygen and carbonnitrogen bonds between aromatic compounds. The substrates used were o-diols from catechols 1, p-quinone 2 from naphthoquinones and naphthohydroquinone 3, which, when activated by the enzyme action, could be reacted with 1,3-diketones 4, 5 or coumarins 6 (Figure 1). The aim of synthesising different classes of compounds was to vary the functional groups and to increase the number of rings, so as to possibly increase the biological activities