Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies

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Abstract

Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.

Original languageEnglish (US)
Pages (from-to)9492-503
Number of pages12
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number36
DOIs
StatePublished - Sep 28 2015

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Keywords

  • Anti-Bacterial Agents
  • Antifungal Agents
  • Candida albicans
  • Cell Line, Tumor
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Gram-Negative Bacteria
  • Humans
  • Macrocyclic Compounds
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Peptidomimetics
  • Quantitative Structure-Activity Relationship
  • Journal Article
  • Research Support, Non-U.S. Gov't

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