Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies
| Autor: | Wolfgang Sippl, Stefan Wagner, Jelena Melesina, Burkhard Riemann, Hélène Van de Vyver, Dmitrii V. Kalinin, Bettina Löffler, Ralph Holl, Michael Schäfers, Oriana Agoglitta |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Proline
Tertiary amine Stereochemistry Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests Matrix metalloproteinase Hydroxamic Acids 01 natural sciences Biochemistry Amidohydrolases Structure-Activity Relationship chemistry.chemical_compound Bacterial Proteins Catalytic Domain Gram-Negative Bacteria Drug Discovery Escherichia coli Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Binding Sites biology 010405 organic chemistry Chemistry Organic Chemistry biology.organism_classification Anti-Bacterial Agents 0104 chemical sciences Molecular Docking Simulation Zinc 010404 medicinal & biomolecular chemistry Enzyme Chiral pool synthesis Docking (molecular) Molecular Medicine Selectivity Bacteria |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:1997-2018 |
| ISSN: | 0968-0896 |
| Popis: | The Zn2+-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel d - and l -proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the l -proline-based tertiary amine 41g ((S)-N-hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (Ki = 1.4 μM) over several human MMPs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect