Browsing by Author "Watermeyer, Nicholas D"

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    Bioactive chloroquine-based ligands and their gold complexes as potential novel antimalarial agents
    (2008) Watermeyer, Nicholas D; Chibale, Kelly
    Chloroquine(CO)-derived 4-aminoquinolines have proven to be the most efficacious antimalarial drugs for both the treatment and prophylaxis of malaria. However, with the advent of drug resistance, their ability to treat the disease has been significantly hindered. Future research into the synthesis of new 4-aminoquinoline derivatives is warranted, since it has been found that the resistance is based on the identity of the side chain and not on the aminoquinoline ring, the functionality by which these compounds derive their activity. Consequently, the synthesis of CO derivatives with a modified side chain attached to a substituted quinoline ring is a reasonable approach in the search of novel antimalarial compounds that are active against drug-resistant parasite strains.
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    Design and synthesis of potential inhibitors of enzymes involved in the biosynthesis and utilisation of mycothiol
    (2012) Watermeyer, Nicholas D; Gammon, David W; Steenkamp, Daniel
    This thesis describes the synthesis of several naphthoquinone- and carbazole-1,4-quinone-derived conjugates of a mycothiol-like scaffold designed to act as redox cycling subversive substrates of the enzyme, Mtr, or potentially inhibit other mycothiol-dependent or biosynthetic enzymes, in order to develop novel antitubercular lead compounds. The expression and purification of Mtr, as well as the attempts made towards the cloning and expression of active Mycobacterial glyoxalase I, in order to generate enzymes on which to assay the synthesised molecules, are also described. Linking of the quinone functionalities to the mycothiol-like scaffold, phenyl-1-thio-Dglucosamine, was envisaged to facilitate delivery of this class of redox active molecules to the active-site of the mycothiol enzymes. Successful completion of the synthesis of naphthoquinone conjugates of this scaffold was not achieved due to a persistent side reaction that took place during an N-tert-butoxycarbonyl deprotection step. However, this unexpected result led to the discovery of a new synthetic route to benzo[g]indoles and benzo[h]quinolines. This route differs from traditional quinoline and indole syntheses in that the aromatic C-N bond is generated by a condensation reaction between a quinone carbonyl and an aliphatic amine, rather than via the traditional condensation of an aromatic amine with a distal carbonyl group.