Mur ligases inhibitors with azastilbene scaffold: Expanding the structure-activity relationship

Martina Hrast; Rok Frlan; Damijan Knez; Irena Zdovc; Hélène Barreteau; Stanislav Gobec

doi:10.1016/j.bmcl.2021.127966

Mur ligases inhibitors with azastilbene scaffold: Expanding the structure-activity relationship

Bioorg Med Chem Lett. 2021 May 15:40:127966. doi: 10.1016/j.bmcl.2021.127966. Epub 2021 Mar 17.

Authors

Martina Hrast¹, Rok Frlan², Damijan Knez², Irena Zdovc³, Hélène Barreteau⁴, Stanislav Gobec⁵

Affiliations

¹ Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: martina.hrast@ffa.uni-lj.si.
² Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
³ Veterinary Faculty, University of Ljubljana, Gerbičeva ulica 60, SI-1000 Ljubljana, Slovenia.
⁴ Bacterial Cell Envelopes and Antibiotics Group, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
⁵ Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.

PMID: 33744441
DOI: 10.1016/j.bmcl.2021.127966

Abstract

Antibiotic resistance represents one of the biggest public health challenges in the last few years. Mur ligases (MurC-MurF) are involved in the synthesis of UDP-N-acetylmuramyl-pentapeptide, the main building block of bacterial peptidoglycan polymer. They are essential for the survival of bacteria and therefore important antibacterial targets. We report herein the synthesis and structure-activity relationships of Mur ligases inhibitors with an azastilbene scaffold. Several compounds showed promising inhibitory potencies against multiple ligases and one compound also possessed moderate antibacterial activity. These results represent a solid ground for further development and optimization of structurally novel antimicrobial agents to combat the rising bacterial resistance.

Keywords: Antibacterial agents; Bacterial cell wall; Multiple inhibitors; Mur ligases; Stilbenes.

Publication types

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Benzylidene Compounds / chemical synthesis
Benzylidene Compounds / metabolism
Benzylidene Compounds / pharmacology*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Molecular Docking Simulation
Molecular Structure
Peptide Synthases / antagonists & inhibitors*
Peptide Synthases / metabolism
Protein Binding
Pyridines / chemical synthesis
Pyridines / metabolism
Pyridines / pharmacology*
Staphylococcus aureus / drug effects
Staphylococcus aureus / enzymology
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Bacterial Proteins
Benzylidene Compounds
Enzyme Inhibitors
Pyridines
Peptide Synthases