Antibacterial peptidomimetics based on guanidine-functionalized di-tertiary amides

Area of Science:

• Medicinal Chemistry
• Peptidomimetics
• Antimicrobial Agents

Background:

• Tertiary amides, like peptoids, are advanced peptidomimetics offering improved stability and activity over natural antimicrobial peptides.
• Guanidino compounds are recognized for their cell-penetrating properties, making them attractive in drug development.
• Combining peptoid backbone properties with guanidine's cell-penetrating ability and antimicrobial peptide (AMP)-like features is a novel strategy.

Purpose of the Study:

• To investigate the impact of modifying guanidino groups on the antibacterial activity of tertiary amides.
• To design and synthesize a library of guanidinium tertiary amides incorporating lipophilic, hydrophobic, and cationic features.
• To evaluate the antibacterial efficacy, biofilm disruption capabilities, and safety profile of these novel compounds.

Main Methods:

• Design and synthesis of a library of bromo-phenyl and dichloro-phenyl-based guanidinium tertiary amides.
• Determination of minimum inhibitory concentrations (MICs) against *Staphylococcus aureus*, *Escherichia coli*, and *Pseudomonas aeruginosa*.
• Assessment of biofilm disruption activity, membrane permeability, and cytotoxicity (HC50).

Main Results:

• Compounds with guanidine bearing 3C and 6C alkylated cationic groups (19a, 20a, 19b, 20b) demonstrated the highest activity against all tested bacterial strains.
• MIC values ranged from 1-2 μg mL^-1 for *S. aureus*, 4-8 μg mL^-1 for *E. coli*, and 16.5-35.6 μg mL^-1 for *P. aeruginosa*.
• Compound 19b effectively disrupted *S. aureus* biofilms (75%), and compound 19g disrupted *E. coli* biofilms (50%). Membrane studies indicated cell membrane depolarization and disruption. The most potent compounds showed no toxicity (HC50 > 50 μg mL^-1).

Conclusions:

• Modified guanidinium tertiary amides exhibit potent broad-spectrum antibacterial activity and significant biofilm disruption capabilities.
• The incorporation of specific cationic group lengths (3C and 6C) is crucial for optimizing antimicrobial efficacy.
• These peptoid-based compounds represent a promising, non-toxic class of novel antimicrobial agents with potential therapeutic applications.