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.

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

“…Especially, this compound also displayed significantly diminished hemolytic potency. Further research implied that the high potency of 143 might arise from the higher basicity of the imidazole ring (p K α = 7.0), and replacement of the imidazole ring with weaker basic triazole ring (p K α = 1.2) decreased the bioactivity …”

Scaling the Amphiphilic Character and Antimicrobial Activity of Gramicidin S by Dihydroxylation or Ketal Formation

“…Its amphiphilic character with the aliphatic Val and Leu side chains oriented to one side and the cationic Orn side chains to the opposite direction forms the basis for the antimicrobial activity of GS toward a wide range of Gram-positive and Gram-negative bacteria by interacting with the lipid bilayer, lowering its integrity and ultimately causing cell death. − Bacterial resistance develops more slowly against antibiotics targeting the cell membrane than against other modes of action, but the unwanted hemolytic activity restricts the use of GS beyond topical applications. , In spite of the many efforts and numerous GS analogues which were synthesized in the past 40 years, it was not possible to separate and suppress this unspecific membrane activity in a structure-based approach. Several investigations report ring contractions, ring expansions, mutations in the β-sheet and in the β-turn region, natural or non-natural amino acids, and their influence on the antimicrobial and hemolytic activity of GS . − Here, we describe a novel approach to the problem of unspecific membrane affinity of GS: We systematically scale its membrane affinity by linking the peptide with different types of membrane anchors in a modular way. We introduce Dyp at the position of Pro as the smallest possible dihydroxylation of GS .…”

Triazole- and Tetrazole-Bridged Nucleic Acids: Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro and in Vivo Antisense Potency

“…As an alternative, we investigated construction of the bridged structure by an S N 2 reaction after introduction of the triazole unit on the 4′-carbon. As shown in Scheme , Huisgen reaction of 1 with 2,4-dimethoxybenzyl (DMB) azide gave 5 . Triflation of 5 and subsequent removal of the DMB group with TFA afforded 7 .…”

“…Pyridine (0.047 mL, 0.579 mmol) and trifluoromethanesulfonic anhydride (Tf 2 O) (0.044 mL, 0.263 mmol) were added to a solution of compound 1 (81 mg, 0.175 mmol) in CH 2 Cl 2 (0.8 mL) at 0 °C, and the mixture was stirred at the same temperature for 1 h. After addition of water, the mixture was extracted with EtOAc. The organic extracts were washed with 10% citric acid solution, water, and brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to give crude compound 2 (113 mg).…”