title: Evaluation of readily accessible azoles as mimics of the aromatic ring of D-phenylalanine in the turn region of gramicidin S.
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.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Gorlaeus laboratories, Leiden, The Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: van der Knaap
authors.forename: Lianne T
authors.initials: LT
authors.lastname: Lageveen
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Busscher
authors.forename: Roos
authors.initials: R
authors.lastname: Mars-Groenendijk
authors.forename: Daan
authors.initials: D
authors.lastname: Noort
authors.forename: José M
authors.initials: JM
authors.lastname: Otero
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Llamas-Saiz
authors.forename: Mark J
authors.initials: MJ
authors.lastname: van Raaij
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006096:Gramicidin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010649:Phenylalanine / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D014230:Triazoles; D006096:Gramicidin; D010649:Phenylalanine