TB is the second leading cause of morbidity world wide caused by a single infectious organism. One third of the world's population are infected with the causative agent, Mycobacterium tuberculosis, and every year it kills 1.7 million people. There is an urgent need to find new Anti - TB that are efficacious, affordable and compatible with HIV and other Anti - TB used in developing countries, where the disease is prevalent. These drugs must also shorten treatment time and be active against resistant forms of the mycobacteria that will help increase patient compliance. One such lead compound which may be developed to meet these criteria is thiolactomycin (TLM). This naturally occurring antibiotic has been shown to be active against M tuberculosis by inhibiting the F AS 11 condensing enzymes mtFabH, KasA and KasB involved in mycolic acid biosynthesis. We thus embarked on a project to design and synthesize analogues of TLM, and related compounds, as new lead molecules for consideration as potential Anti - TB. A series of synthetic procedures, amenable for use in an iterative drug design process, were postulated and investigated to generate enantiomerically pure analogues of TLM derivatised at the third and fifth positions of the thiolactone ring. The first was using a method starting from D-alanine which generated a pair of diastereoisomers which could be separated to give both enantiomers as analogues. However, this route depended upon the production of enantiomerically pure (S)-thiolactic acid which could not be isolated. However, it was possible to obtain racemic analogues using this approach. A second strategy was attempted by the chiral resolution of racemic thiolactic acid to generate a series of organic salts.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:501828 |
| Date | January 2009 |
| Creators | Bensaber, Salah M. |
| Publisher | University of Strathclyde |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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