Efficient synthesis of a bacterial translocase MraY inhibitor

The bacterial translocase MraY has recently been demonstrated as a prime target for the development of new antibiotics. We describe a straightforward synthesis of a new inhibitor 1 of this enzyme. The two key steps involve a tandem nucleophilic epoxide ring opening of C2-symmetrical bis-epoxide and subsequent O-heterocyclisation, followed by O-glycosylation. The in vitro biological evaluation of 1 at 2 mM showed an 81% of inhibition of the MraY activity. Therefore, congeners of 1 should permit detailed SAR investigations for the discovery of novel antibacterials.

Graphical abstractThe synthesis of a powerful inhibitor of the bacterial translocase MraY (81% inhibition at 2 mM) is described.Figure optionsDownload full-size imageDownload as PowerPoint slide

2,5-Anhydro-3,4-di-O-benzyl-1-deoxy-1-(uracil-1′-yl)-d-glucitolC24H26N2O6De >95% (by 1H NMR)[α]D20=-8 (c 1.0, CH3OH)Source of chirality: 1,2:5,6-dianhydro-3,4-di-O-benzyl-l-iditol

2,5-Anhydro-1-deoxy-6-O-(5″-azido-5″-deoxy-2″,3″-O-isopentylidene-β-d-ribofuranosyl)-1-(uracil-1′-yl)-3,4-di-O-benzyl-d-glucitolC34H41N5O9De >95% (by 1H NMR)[α]D20=-28 (c 1.0, CH3OH)Source of chirality: 1,2:5,6-dianhydro-3,4-di-O-benzyl-l-iditol and d-ribose

2,5-Anhydro-1-deoxy-6-O-(5″-azido-5″-deoxy-β-d-ribofuranosyl)-1-(uracil-1′-yl)-3,4-di-O-benzyl-d-glucitolC29H33N5O9De >95% (by 1H NMR)[α]D20=-6 (c 1.0, CH3OH)Source of chirality: 1,2:5,6-dianhydro-3,4-di-O-benzyl-l-iditol and d-ribose

2,5-Anhydro-1-deoxy-6-O-(5″-amino-5″-deoxy-β-d-ribofuranosyl)-1-(uracil-1′-yl)-d-glucitolC15H23N3O9De >95% (by 1H NMR)[α]D20=-33 (c 1.0, H2O)Source of chirality: 1,2:5,6-dianhydro-3,4-di-O-benzyl- l-iditol and d-ribose