Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline.

This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.

• Publication year

  2018

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2018-09-18

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.8b01287PMID 30226381
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Structure-based discovery of LpxC inhibitors.

  2017cited by this paper
• Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.

  2017cited by this paper
• Recent Advances in Scaffold Hopping.

  2017cited by this paper
• LpxC inhibitors: a patent review (2010-2016)

  2017cited by this paper
• Inhibition of LpxC Increases Antibiotic Susceptibility in Acinetobacter baumannii

  2016cited by this paper
• Recent Process in the Inhibitors of UDP-3-O-(R-3-hydroxyacyl)-Nacetylglucosamine Deacetylase (LpxC) Against Gram-Negative Bacteria.

  2016cited by this paper
• Biosynthesis and export of bacterial lipopolysaccharides.

  2014cited by this paper
• Bacterial lipids: metabolism and membrane homeostasis.

  2013cited by this paper
• The rise of carbapenem resistance in Europe: just the tip of the iceberg?

  2013cited by this paper
• Simulated single-cycle kinetics improves the design of surface plasmon resonance assays.

  2013cited by this paper
• Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents.

  2012cited by this paper
• ZINC: A Free Tool to Discover Chemistry for Biology

  2012cited by this paper
• Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

  2012cited by this paper
• Potent inhibitors of LpxC for the treatment of Gram-negative infections.

  2012cited by this paper
• Inhibition of LpxC Protects Mice from Resistant Acinetobacter baumannii by Modulating Inflammation and Enhancing Phagocytosis

  2012cited by this paper
• Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections.

  2012cited by this paper
• Critical shortage of new antibiotics in development against multidrug-resistant bacteria-Time to react is now.

  2011cited by this paper
• ChEMBL: a large-scale bioactivity database for drug discovery

  2011cited by this paper
• Heteroaromatic rings of the future.

  2009cited by this paper
• Drugs for bad bugs: confronting the challenges of antibacterial discovery

  2007cited by this paper
• Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli.

  2007cited by this paper
• Lipid A modification systems in gram-negative bacteria.

  2007cited by this paper
• Molecular Field Extrema as Descriptors of Biological Activity: Definition and Validation

  2006cited by this paper
• Molecular Validation of LpxC as an Antibacterial Drug Target in Pseudomonas aeruginosa

  2006cited by this paper
• Scaffold hopping through virtual screening using 2D and 3D similarity descriptors: ranking, voting, and consensus scoring.

  2006cited by this paper
• A 3D similarity method for scaffold hopping from known drugs or natural ligands to new chemotypes.

  2004cited by this paper
• Antibacterial Agents That Inhibit Lipid A Biosynthesis

  1996cited by this paper
• The envA Permeability/Cell Division Gene of Escherichia coli Encodes the Second Enzyme of Lipid A Biosynthesis

  1995cited by this paper
• Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction

  1993cited by this paper
• The lipid A biosynthesis mutation lpxA2 of Escherichia coli results in drastic antibiotic supersusceptibility

  1992cited by this paper
• Bacterial endotoxin and current concepts in the diagnosis and treatment of endotoxaemia.

  1990cited by this paper

• Fluoroquinolones as Versatile Scaffolds: Potential for Targeting Classical and Novel Mechanisms to Combat Antibacterial Resistance.

  2025cites this paper
• Research progress of LpxC inhibitor on Gram-negative bacteria.

  2025cites this paper
• Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024)

  2025cites this paper
• Synthesis of 3-Benzoylisoxazolines by Copper(Ⅰ) Bromide-Catalyzed 1,3-Dipolar Cycloaddition of Nitroketones with Dipolarophiles

  2025cites this paper
• Scaffold hopping approaches for dual-target antitumor drug discovery: opportunities and challenges

  2024cites this paper
• A new investigation into the regioselectivity and stereoselectivity of the reaction between di-methyl nitrone and fluorinated alkenes: DFT, independent gradient model, and molecular docking

  2024cites this paper
• Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives

  2023cites this paper
• Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

  2023cites this paper
• Oxazolidinones as versatile scaffolds in medicinal chemistry

  2023cites this paper
• Rational design, synthesis, molecular modeling, biological activity, and mechanism of action of polypharmacological norfloxacin hydroxamic acid derivatives

  2023cites this paper
• Small molecule LpxC inhibitors against gram-negative bacteria: Advances and future perspectives.

  2023cites this paper
• Network Analysis Guided Designing of Multi-Targeted Anti-Fungal Agents: Synthesis and Biological Evaluation

  2022cites this paper
• Room Temperature Cu-Catalyzed N-Arylation of Oxazolidinones and Amides with (Hetero)Aryl Iodides.

  2022cites this paper
• High-Throughput Screen for Inhibitors of Klebsiella pneumoniae Virulence Using a Tetrahymena pyriformis Co-Culture Surrogate Host Model

  2022cites this paper
• Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.

  2022cites this paper
• Recent Advances in Nonprecious Metal Catalysis

  2021cites this paper
• 1,3-Dipolar cycloaddition of N-allyl substituted polycyclic derivatives of isoindole-1,3-dione with nitrones and nitrile oxides: An experimental and theoretical investigation

  2020cites this paper
• VSPrep: A KNIME workflow for the preparation of molecular databases for virtual screening.

  2020cites this paper
• Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis.

  2020cites this paper
• Acetylene Group, Friend or Foe in Medicinal Chemistry.

  2020cites this paper
• Recently developed synthetic compounds with anti-infective activity.

  2019cites this paper
• Synthesis, antibacterial and anticancer activity, and docking study of aminoguanidines containing an alkynyl moiety

  2019cites this paper
• Discovery of Novel Inhibitors of LpxC Displaying Potent In Vitro Activity against Gram-Negative Bacteria.

  2019cites this paper
• Mutations Reducing In Vitro Susceptibility to Novel LpxC Inhibitors in Pseudomonas aeruginosa and Interplay of Efflux and Nonefflux Mechanisms

  2019cites this paper
• Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis

  2019cites this paper
• Discovery of Novel N-Isoxazolinylphenyltriazinones as Promising Protoporphyrinogen IX Oxidase Inhibitors.

  2019cites this paper