title: Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors.
abstract: 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 d-mannose, 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 Ki-values of 0.35 μm and 0.23 μm, the (S,S)-configured open-chain derivatives 8b and 8c were found to be the most potent LpxC inhibitors of these series of compounds.
authors: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany.
authors: Hannes
authors: H
authors: Müller
authors: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany.
authors: Valeria
authors: V
authors: Gabrielli
authors: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany; NRW Graduate School of Chemistry, University of Münster, Germany.
authors: Oriana
authors: O
authors: Agoglitta
authors: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstr. 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Germany. Electronic address: hollr@uni-muenster.de.
authors: Ralph
authors: R
authors: Holl
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D008358:Mannose / Q000031:analogs & derivatives / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006027:Glycosides; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; D008358:Mannose
keywords: Benzyloxyacetohydroxamic acids; C-glycosides; Chiral pool synthesis; LpxC inhibitors; Structure-activity relationships