Antibacterial peptidomimetics based on guanidine-functionalized di-tertiary amides

Abstract

Tertiary amides such as peptoids are a novel class of peptidomimetics that offer enhanced structure, activity, and stability compared to many naturally occurring antimicrobial peptides. Guanidino compounds have gained interest in medicinal chemistry as cell-penetrating molecules. This work investigates the changes in the antibacterial activity of modified guanidino groups on the structure of active guanidino tertiary amides by incorporating lipophilic, hydrophobic, and extra cationic groups, thereby combining the properties of the tertiary amide in the peptoid backbone with the important role of addition of extra cationic and lipophilic residues, such as those in AMPs, but supported by guanidine backbones. A library of active antibacterial bromo-phenyl and dichloro-phenyl-based guanidinium tertiary amides, including three series, was designed. These compounds exhibited MICs of 1–2 μg mL⁻¹, 4–8 μg mL⁻¹, and 16.5–35.6 μg mL⁻¹ against S. aureus, E. coli, and P. aeruginosa, respectively. Tertiary amides with their guanidine bearing an alkylated cationic group of 3C (19a and 20a) and 6C (19b and 20b) length resulted in the most active molecules against all tested strains. Additionally, at 8× MIC, compound 19b was the most effective S. aureus biofilm disruptor, disrupting 75% of the biofilm, while compound 19g was the most active molecule against E. coli biofilm, with 50% disruption. The membrane permeability and QCM-D studies suggested that the designed cationic tertiary amides could depolarize and disrupt the bacterial cell membrane. The most potent peptoids were non-toxic, with HC₅₀ of more than 50 μg mL⁻¹.