Synthesis, Biological Evaluation, and Molecular Docking Studies of 2r,3t,4c-Configured C-Furanosidic LpxC Inhibitors

In chiral pool syntheses starting from d-mannitol and d-galactose, a series of four 2r,3t,4c-configured C-furanosides was accessed. The synthesized stereoisomeric hydroxamic acids were tested for antibacterial activity as well as inhibitory potency toward the bacterial deacetylase LpxC, a promising target for antibiotics selectively targeting Gram-negative bacteria. The obtained biological data were compared with those of the previously synthesized 12 stereoisomers, and molecular docking as well as molecular dynamics studies were performed to rationalize the observed structure-activity relationships. Initial in vitro ADMET studies revealed excellent microsomal metabolic and plasma stability of the investigated C-furanosides.