Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents

Org Biomol Chem. 2015 Jun 14;13(22):6225-41. doi: 10.1039/c5ob00621j.

Abstract

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL(-1) against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cations / chemical synthesis
  • Cations / chemistry
  • Cations / pharmacology
  • Dose-Response Relationship, Drug
  • Gram-Negative Bacteria / drug effects*
  • Gram-Positive Bacteria / drug effects*
  • Microbial Sensitivity Tests
  • Norbornanes / chemical synthesis
  • Norbornanes / chemistry
  • Norbornanes / pharmacology*
  • Peptidomimetics*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Cations
  • Norbornanes
  • Peptidomimetics