Design and synthesis of antitubercular agents
Abstract
Tuberculosis (TB) is a life-threatening disease which has plagued humans for centuries. Despite significant advances in modern medicine for tackling diseases, treatment of TB infections remains a challenging task: 6-12 months of treatment are required with daily dosing of up to 6 different antibiotics. The World Health Organisation (WHO) has placed the causative agent Mycobacterium tuberculosis (M. tb) on a priority list for novel drug development which led to an explosion of research in this field. The electron transport chain (ETC) within M. tb has become a desirable drug target, with the thought that inhibition of this process would result in rapid bacterial killing and shorter treatment time. The oxidoreductase enzymes, cytochrome (cyt) bc and bd, are redundant. Therefore, simultaneous inhibition of these enzymes is required to induce a bactericidal effect. There are efficacious and safe cyt bc inhibitors, however, a synergistic cyt bd inhibitor is yet to be discovered. This thesis focuses on the development of cyt bd inhibitors, and methods to release a payload capable of simultaneous cyt bc and cyt bd inhibition. In Chapter 2, the development of a structure activity relationship (SAR) between the reference natural product for cyt bd inhibition, aurachin D (AuD), and cyt bd is discussed. A series of analogues exhibiting aromatic substitutions, alkyl chain modifications, or quinolone modifications were synthesised. The half-maximal inhibitory concentration (IC50) for…
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