Evaluation of Readily Accessible Azoles as Mimics of the Aromatic Ring of D-Phenylalanine in the Turn Region of Gramicidin S

Matthijs van der Knaap*, Lianne T. Lageveen, Henk J. Busscher, Roos Mars-Groenendijk, Daan Noort, Jose M. Otero, Antonio L. Llamas-Saiz, Mark J. van Raaij, Gijsbert A. van der Marel, Herman S. Overkleeft, Mark Overhand

*Corresponding author for this work

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14 Citations (Scopus)

Abstract

The influence of replacing the D-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidin S was investigated against a representative panel of Gram-positive and Gram-negative bacteria strains. Substituted triazole derivatives, obtained using a convergent synthetic strategy, are as active as gramicidin S, provided that any substituent on the triazole moiety is not too large. The unsubstituted triazole derivative was biologically less active than the parent natural product, gramicidin S. In general for the triazole series, the hemolytic activity could be correlated with the antibacterial activity, that is, the higher the antibacterial activity, the higher the toxicity towards blood cells. Interestingly, its imidazole counterpart showed high antibacterial activity, combined with significantly diminished hemolytic activity.

Original languageEnglish
Pages (from-to)840-847
Number of pages8
JournalChemMedChem
Volume6
Issue number5
DOIs
Publication statusPublished - 2-May-2011

Keywords

  • antibacterial activity
  • azole
  • gramicidin S
  • hemolytic activity
  • peptides
  • CATIONIC ANTIMICROBIAL PEPTIDES
  • HEMOLYTIC-ACTIVITY
  • DIFFRACTION DATA
  • BIOLOGICAL-ACTIVITY
  • TERMINAL ALKYNES
  • SOLID-PHASE
  • AMINO-ACID
  • ANALOGS
  • ANTIBACTERIAL
  • CONFORMATION
  • CCDC 804272: Experimental Crystal Structure Determination

    van der Knaap, M. (Contributor), Lageveen, L. (Contributor), Busscher, H. (Contributor), Mars-Groenendijk, R. (Contributor), Noort, D. (Contributor), Otero, J. M. (Contributor), Llamas-Saiz, A. L. (Contributor), van Raaij, M. J. (Contributor), van der Marel, G. A. (Contributor), Overkleeft, H. S. (Contributor) & Overhand, M. (Contributor), University of Groningen, 9-Dec-2010

    Dataset

  • CCDC 804273: Experimental Crystal Structure Determination

    van der Knaap, M. (Contributor), Lageveen, L. (Contributor), Busscher, H. (Contributor), Mars-Groenendijk, R. (Contributor), Noort, D. (Contributor), Otero, J. M. (Contributor), Llamas-Saiz, A. L. (Contributor), van Raaij, M. J. (Contributor), van der Marel, G. A. (Contributor), Overkleeft, H. S. (Contributor) & Overhand, M. (Contributor), University of Groningen, 9-Dec-2010

    Dataset

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