1-C-phosphonomethyl- and 1-C-difluorophosphonomethyl-1,4-imino-l-arabinitols as Galf transferase inhibitors: A comparison

The convenient preparation of iminopentitol derivatives, based on a 1,4-dideoxy-1,4-imino-l-arabinitol scaffold carrying β-phosphono(difluoromethyl) or β-phosphonomethyl appendages, as Galf-1P mimics, is reported. The compounds were tested for their ability to inhibit GlfT2, a vital galactofuranosyltransferase involved in the cell wall biosynthesis of mycobacteria. Interestingly, the Galf-1P mimics lacking a fluorine atom (7 and 8) were very poor inhibitors, showing less than 20% inhibition of GlfT2, whereas compounds 2 and 3, which contains a difluoromethylenephosphonate moiety were more potent inhibitors. Compound 3 that is fully deprotected was the most potent showing a significant IC50 value (0.9 mm), despite the absence of the diphosphate linkage present in the parent sugar nucleotide. This study paves the way to the synthesis of more complex β-phosphonomethyl-imino-l-arabinitol derivatives as simplified mimics of UDP-α-d-Galf. [Display omitted] •Synthesis of imino-l-arabinitols with (non)-fluorinated phosphonomethyl appendages.•The compounds behave as Galf-1P mimics and inhibitors of GlfT2.•Galf-1P mimics with a difluoromethylenephosphonate moiety are more potent inhibitors.•The study paves the way to the synthesis of more complex mimics of UDP-α-d-Galf.