Design and Synthesis of Antimycobacterial Agents

Abstract

Antibiotics have revolutionised modern life, however growing antimicrobial resistance threatens the advantages we have become accustomed to. Since the Golden Age of antibiotic drug discovery in the mid-20th century, progress has been tepid with target-based screens of synthetic and structurally conservative compound libraries failing to produce new therapeutics. This has led to a renewed interest in utilising phenotypic screens, but rather than applying them to natural product libraries and running the risk of rediscovering known antibiotics, applying them to novel compound libraries which explore more chemical space. After its extensive work in diversity-oriented synthesis, the Spring group has developed such a library. A collection of these compounds was evaluated in a phenotypic screen against Mycobacterium abscessus, producing four lead compounds, two of which, 13H8 and 14F8, were chosen for further development. The first project in this dissertation aimed to improve the biological activity of the propiolic ester lead 13H8, by building on existing knowledge of its structure-activity relationship (SAR). The first generation of compounds successfully produced a compound which improved on previous activity, and established that the degree to which the ester linkage impacts activity is more substrate specific than previously recognised. Further exploration of the new lead in the second generation of compounds failed to improve on its activity, but has given results which will inform future SAR efforts. The second project in this dissertation aimed to evaluate routes towards accessing the poly-substituted indole lead 14F8 to enable an SAR study. Multiple routes were evaluated, with two providing potential ways towards accessing the 2-, 5- and 7-positions of the indole simultaneously. Compounds synthesised in this process were biological evaluated, giving an initial SAR of the structure. This has shown that having an aliphatic chain at the 7-position is essential for activity.