Synthesis of mannosides as potential inhibitors of PIMs biosynthesis in mycobacteria

The discovery of new therapeutic targets for combating tuberculosis has become crucial due to the alarming increase in multi-drug resistant strains. The acyltransferase PatA, involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs), key components of the mycobacterial cell wall, has recently been shown to be essential for mycobacterial growth. This enzyme therefore represents a promising potential therapeutic target. We report here the design and synthesis of mannosides, as PIM₁ analogues and potential PatA inhibitors, bearing at the anomeric position a surrogate of the phosphatidylinositol moiety and, at the 6-position, a fluorine atom or a sulfonamide or phosphonate group mimicking the tetrahedral transition state of the acylation reaction.