Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-based γ-peptide oligomers named ATCs as tunable scaffolds to design polycationic AMP mimetics. Knowing the side chain distribution along the backbone, we rationally designed facially amphiphilic sequences with bactericidal effect in the micromolar range. Since no hemolytic activity was detected up to 100 μM, this class of compounds has shown the potential for therapeutic development.

4‐Amino(methyl)‐1,3‐thiazole‐5‐carboxylic acids (ATCs) are a new class of constrained heterocyclic γ‐amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β‐sheets, turns, and β‐hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross‐Claisen condensations between N‐Fmoc‐amino acids and sterically hindered 1,1‐dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N‐Fmoc‐β‐keto ester intermediates were engaged in a two‐step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ‐carbon atom or on the thiazole core of the γ‐amino acids.

Nuclear magnetic resonance (NMR) spectroscopy has been established as a potent method for the determination of foldamer structures in solution. However, the NMR techniques could be limited by averaging, so additional experimental techniques are often needed to fully endorse the folding properties of a sequence. We have recently demonstrated that oligo-γ-peptides composed of 4-amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) adopt an original helical fold stabilized by hydrogen bonds forming C pseudocycles. The main objective of the present work is to reinvestigate the folding of ATC oligomer 1 in order to identify reliable FT-IR and NMR structural markers that are of value for tracking the degree of organization of ATC-based peptides.