Synthesis of mannosides as potential inhibitors of PIMs biosynthesis in mycobacteria.

Abstract

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.