Mycobacterium tuberculosis (Mtb) is a leading cause of bacterial infectious disease-related deaths worldwide. Drug resistant Mtb strains necessitate the development of novel antibiotics. Biotin Protein Ligase (MtBPL) is an essential enzyme in Mtb required for lipid metabolism. We recently reported a series of potent biotin-adenosine bisubstrate inhibitors of MtBPL that differed at the ribofuranosyl moiety of adenosine.1 Although all of the inhibitors were nontoxic in cell culture, potential in vivo metabolism could liberate 5'-sulfamoylated nucleosides, some of which have notable toxicity through inhibition of mammalian protein synthesis.2 The purpose of this study was to identify non-toxic sulfamoylated nucleoside analogs for incorporation in our bisubstrate inhibitors. We will describe the synthesis of a series of sulfamoylated nucleoside breakdown products of our described MtBPL inhibitors, and evaluation of each compound for inhibition of protein synthesis using an in vitro translation assay, and cytotoxicity against a panel of mammalian cell lines.

Synthesis and biological evaluation of sulfamoylated adenine nucleosides

251st National Meeting (2016)

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