Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors

Inhibitors of the bacterial deacetylase LpxC have emerged as a promising new class of Gram-negative selective antibacterials. In order to find novel LpxC inhibitors, in chiral-pool syntheses starting from Dmannose, C-furanosides with altered configuration in positions 2 and/or 5 of the tetrahydrofuran ring were prepared in stereochemically pure form. Additionally, the substitution pattern in positions 3 and 4 of the tetrahydrofuran ring as well as the structure of the lipophilic side chain in position 2 were varied. Finally, all stereoisomers of the respective open chain diols were obtained via glycol cleavages of properly protected C-glycosides. The biological evaluation of the synthesized hydroxamic acids revealed that in case of the C-glycosides, 2,5-trans-configuration generally leads to superior inhibitory and antibacterial activities. The relief of the conformational strain leading to the respective open chain derivatives generally caused an increase in the inhibitory and antibacterial activities of the benzyloxyacetohydroxamic acids. With K-i-values of 0.35 mu m and 0.23 mu M, the (S,S)-configured open-chain derivatives 8b and 8c were found to be the most potent LpxC inhibitors of these series of compounds. (C) 2016 Elsevier Masson SAS. All rights reserved.