Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies

Dmitrii V Kalinin; Oriana Agoglitta; Hélène Van de Vyver; Jelena Melesina; Stefan Wagner; Burkhard Riemann; Michael Schäfers; Wolfgang Sippl; Bettina Löffler; Ralph Holl

doi:10.1016/j.bmc.2019.03.056

Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies

Bioorg Med Chem. 2019 May 15;27(10):1997-2018. doi: 10.1016/j.bmc.2019.03.056. Epub 2019 Mar 30.

Authors

Affiliations

¹ Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Germany.
² Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; NRW Graduate School of Chemistry, University of Münster, Germany.
³ Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Germany; Institute of Medical Microbiology, University Hospital Münster, Domagkstr. 10, 48149 Münster, Germany.
⁴ Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120 Halle (Saale), Germany.
⁵ Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany.
⁶ Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Germany; Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany; European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, 48149 Münster, Germany.
⁷ Institute of Medical Microbiology, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany.
⁸ Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany. Electronic address: ralph.holl@chemie.uni-hamburg.de.

PMID: 30954331
DOI: 10.1016/j.bmc.2019.03.056

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 (K_i = 1.4 μM) over several human MMPs.

Keywords: Antibacterials; Chiral pool synthesis; LpxC inhibitors; MMP inhibitors; Molecular docking studies; Proline derivatives; Structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidohydrolases / chemistry
Amidohydrolases / metabolism*
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / chemistry
Bacterial Proteins / metabolism*
Binding Sites
Catalytic Domain
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Escherichia coli / drug effects
Escherichia coli / enzymology
Gram-Negative Bacteria / drug effects
Hydroxamic Acids / chemistry*
Microbial Sensitivity Tests
Molecular Docking Simulation
Proline / chemistry*
Proline / metabolism
Structure-Activity Relationship
Zinc / chemistry

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
Hydroxamic Acids
Proline
Amidohydrolases
UDP-3-O-acyl-N-acetylglucosamine deacetylase
Zinc