Design and synthesis of potential inhibitors of enzymes involved in the biosynthesis and utilisation of mycothiol

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.

Grantor dc:publisher.institution

Department of Chemistry

Year dc:date.issued

2012

Author dc:creator

• Watermeyer, Nicholas D

Advisors dc:contributor.advisor

• Gammon, David W
• Steenkamp, Daniel

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/12674

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/12674