Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis,antibacterial properties,and docking studies |
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| Authors: | Dmitrii V Kalinin Oriana Agoglitta Hélène Van de Vyver Jelena Melesina Stefan Wagner Burkhard Riemann Michael Schäfers Wolfgang Sippl Bettina Löffler Ralph Holl |
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| Institution: | 1. Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany;2. German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany;3. Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149 Münster, Germany;4. Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), University of Münster, Germany;5. NRW Graduate School of Chemistry, University of Münster, Germany;6. Institute of Medical Microbiology, University Hospital Münster, Domagkstr. 10, 48149 Münster, Germany;7. Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120 Halle (Saale), Germany;8. Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany;9. European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, 48149 Münster, Germany;10. Institute of Medical Microbiology, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany |
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| Abstract: | 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. |
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| Keywords: | Proline derivatives Chiral pool synthesis Antibacterials LpxC inhibitors Structure-activity relationships Molecular docking studies MMP inhibitors |
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