Evaluation of readily accessible azoles as mimics of the aromatic ring of D-phenylalanine in the turn region of gramicidin S

The influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidinS 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 gramicidinS, 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, gramicidinS. 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. Turning circles! A series of substituted and unsusbstituted azole derivatives of gramicidinS were synthesised, analysed and tested against a range of bacteria and against erythrocytes. The compound where R=H and X=N exhibited high antibacterial and lower hemolytic activities, while a considerable loss of antibacterial activity was observed for the triazole derivative (R=H; X=CH). © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.