Computer-aided drug discovery: Novel 3,9-disubstituted eudistomin U derivatives as potent antibacterial agents

Eur J Med Chem. 2018 Sep 5:157:333-338. doi: 10.1016/j.ejmech.2018.08.001. Epub 2018 Aug 4.

Abstract

Thirty-two new 3,9-disubstituted eudistomin U derivatives were designed and synthesized based on computer-aided drug discovery (CADD). Sixteen 3,9-disubstituted eudistomin U derivatives (6a-6p) have exhibited potent antibacterial activity. Specially, the most active compound 6p displayed better activity than commercial drugs fosfomycin sodium, ciprofloxacin and propineb, with a peak minimum inhibitory concentration (MIC) of 1.5625 μmol/L. The antibacterial mechanism indicated that these compounds could exert bactericidal effect by damaging bacterial cell membrane and disrupting the function of DNA gyrase.

Keywords: Antibacterial; Design; Eudistomin U; Mechanism; Molecular docking; Synthesis.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Carbolines / chemical synthesis
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cell Membrane / drug effects
  • Computer-Aided Design*
  • DNA Gyrase / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / enzymology
  • Gram-Positive Bacteria / drug effects
  • Gram-Positive Bacteria / enzymology
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Carbolines
  • eudistomin U
  • DNA Gyrase