Solution‐Phase Synthesis of Backbone‐Constrained Cationic Peptoid Hexamers with Antibacterial and Anti‐Biofilm Activities

: Submonomer synthesis in solution and block‐coupling protocols were combined to prepare amphiphilic peptoid hexamers. The amphipathic character arises from the use of hydrophobic aliphatic tert‐butyl side‐chains imposing the cis‐amide backbone conformation and various cationic side‐chains periodically introduced each three residues. Evaluation of the effect on Gram‐positive and Gram‐negative bacterial strains as well as the capacity to impair biofilm formation and the toxicity of one selected compound allowed to highlight the potential of a short constrained peptoid carrying triazolium‐type cationic pendant groups. Amphipathic peptoid hexamers carrying hydrophobic aliphatic tert‐butyl side‐chains to impose cis‐amide backbone conformations, and cationic side‐chains periodically introduced every three residues, were synthesized by solution‐phase submonomer method and/or block‐coupling approach. The antibacterial and anti‐biofilm evaluations performed on selected hexamers reveal a much better efficiency of peptoids bearing cationic triazolium groups compared to those with cationic ammonium or triazole groups.