Synthesis of Bioactive Natural Products & Derivatives as Novel Anti-infectives

Throughout history natural products have served as a valuable resource for the treatment of various diseases. To this day, many of these ancient remedies and their derivatives are still in use. However, in recent years, antibiotic discovery has stagnated at a time where there has also been the alarming emergence of antibiotic resistance which threatens to undermine the effectiveness of existing therapies. As such, novel antimicrobial agents are urgently needed that possess unique mechanisms of action to those currently in use. A promising class of natural products that exhibit antimicrobial activity are the non-ribosomal peptides (NRPs). This thesis describes the synthesis and biological evaluation of a number of NRP-derived molecules with a view to discovering new antibiotic leads. Chapters 2 & 3 describe the design and synthesis of potent anti mycobacterial derivatives based on the sansanmycin natural product scaffold. This involved the development of a late stage diversification route, thereby providing a platform for expedient access to a diverse library of analogues. These analogues were subjected to biological evaluation, from which key structure activity relationships were elucidated for inhibition of the growth of Mycobacterium tuberculosis – the etiological agent of tuberculosis (TB). These studies ultimately led to the identification of a new lead compound which was further evaluated in two animal models of TB infection. Chapter 4 describes efforts towards the synthesis of the janthinocins, a class of NRPs with potent activity against Gram positive bacteria. The synthetic strategy relied on late stage, chemoselective transformations to install key functionalities namely, selective oxidation of tryptophan to afford β ketotryptophan and elimination of β methylcysteine to form dehydrobutyrine. A deoxy-variant of janthinocin B was successfully synthesised which was subjected to late stage oxidation to the parent natural product, albeit on a small scale