Design, synthesis and biological evaluation of novel hybrids of N-aryl pyrrothine-base α-pyrone as bacterial RNA polymerase inhibitors

Bioorg Med Chem Lett. 2020 Jun 1;30(11):127146. doi: 10.1016/j.bmcl.2020.127146. Epub 2020 Mar 28.

Abstract

Antibiotic resistance in bacteria has been an emerging public health problem, thus discovery of novel and effective antibiotics is urgent. A series of novel hybrids of N-aryl pyrrothine-base α-pyrone hybrids was designed, synthesized and evaluated as bacterial RNA polymerase (RNAP) inhibitors. Among them, compound 13c exhibited potent antibacterial activity against antibiotic-resistant S. aureus with the minimum inhibitory concentration (MIC) in the range of 1-4 μg/mL. Moreover, compound 13c exhibited strong inhibitory activity against E.coli RNAP with IC50 value of 16.06 μM, and cytotoxicity in HepG2 cells with IC50 value of 7.04 μM. The molecular docking study further suggested that compound 13c binds to the switch region of bacterial RNAP. In summary, compound 13c is a novel bacterial RNAP inhibitor, and a promising lead compound for further optimization.

Keywords: Bacterial RNA polymerase; Hybrid; N-aryl pyrrothine; Switch region; α-pyrone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Candida albicans / drug effects
  • Cell Survival / drug effects
  • DNA-Directed RNA Polymerases / antagonists & inhibitors*
  • DNA-Directed RNA Polymerases / metabolism
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Escherichia coli / enzymology*
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Hep G2 Cells
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Pyrones / chemistry*
  • Pyrones / metabolism
  • Pyrones / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Pyrones
  • DNA-Directed RNA Polymerases