Alkyl-guanidine Compounds as Potent Broad-Spectrum Antibacterial Agents: Chemical Library Extension and Biological Characterization

J Med Chem. 2018 Oct 25;61(20):9162-9176. doi: 10.1021/acs.jmedchem.8b00619. Epub 2018 Oct 11.

Abstract

Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gram-negative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.

MeSH terms

  • Alkylation
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Caco-2 Cells
  • Guanidine / chemistry*
  • Guanidine / metabolism
  • Guanidine / pharmacology*
  • Humans
  • Microbial Sensitivity Tests
  • Permeability
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Guanidine