Synthesis of Antimycobacterial Agents that Harness Mycothiol and Cysteine conjugate β-lyase Metabolic Pathways

Mycobacterium tuberculosis kills approximately two million people each year and is second only to HIV/AIDs in terms of death from infectious disease. The most pertinent problem in regards to Mycobacterium tuberculosis today is the increasing prevalence of drug resistant strains. Thus, there is a great need for the development of new drugs with novel targets. This thesis aimed to address this problem by synthesizing a compound that could exploit the mycothiol detoxification pathway, unique to Mycobacterium, in order to cause cell death, through the release of a harmful halothioketene.  The research described herein involved the successful synthesis of the desired mycothiol analogue, along with three other related compounds. The target compounds were synthesised via protection of N-acetyl glucosamine, followed by thioglycosidation with cyclohexane thiol. Subsequent deprotection and coupling to Boc protected Strichlorovinyl cysteine provided access to the synthetic target and its β-anomer, as well as their Boc protected precursors.  The original synthetic target demonstrated weak antimycobacterial activity against Mycobacterium smegmatis and an encouraging sub 100 μM MIC against Mycobacterium bovis derived Bacillus Calmette–Guérin. Unexpectedly the beta anomer of the synthetic target also displayed antimycobacterial activity against Bacillus Calmette–Guérin (MIC 125 - 250 μM). All compounds proved to be active against HL60 cells (16-114 μM).  Whilst further work is required to improve efficacy, the work presented here demonstrates the potential of these compounds as leads for the generation of new antimycobacterial agents.