Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors
| Autor: | Hannes Müller, Oriana Agoglitta, Valeria Gabrielli, Ralph Holl |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
C glycosides
Stereochemistry Microbial Sensitivity Tests Hydroxamic Acids 010402 general chemistry Ring (chemistry) 01 natural sciences Amidohydrolases Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Escherichia coli Side chain Humans Glycosides Enzyme Inhibitors Escherichia coli Infections Tetrahydrofuran Biological evaluation Pharmacology 010405 organic chemistry Organic Chemistry Stereoisomerism General Medicine Combinatorial chemistry Anti-Bacterial Agents 0104 chemical sciences chemistry Chiral pool synthesis Mannose |
| Zdroj: | European Journal of Medicinal Chemistry. 110:340-375 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2016.01.032 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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