Azirine-containing dipeptides and depsipeptides: synthesis, transformations and antibacterial activity

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Biology

Background:

• Multicomponent reactions (MCRs) offer efficient synthetic routes to complex molecules.
• Azirine derivatives are versatile building blocks in organic synthesis.
• Antibiotic resistance necessitates the development of novel antibacterial agents.

Purpose of the Study:

• To synthesize novel azirine-containing dipeptides and depsipeptides.
• To explore the chemical transformations of these MCR adducts.
• To evaluate the antibacterial potential of the synthesized compounds against ESKAPE pathogens.

Main Methods:

• Utilized Passerini and Ugi multicomponent reactions (MCRs).
• Employed 2H-azirine-2-carboxylic acids as key starting materials.
• Performed subsequent chemical transformations of MCR adducts to various heterocyclic derivatives.

Main Results:

• Achieved high yields in the synthesis of diverse azirine-containing dipeptides and depsipeptides.
• Generated lactam-fused aziridines, pyrroles, imidazoles, and other derivatives.
• Demonstrated significant antibacterial activity of azirine-containing depsipeptides against E. faecium and S. aureus (MICs 16 and 9 μg mL-1, respectively).

Conclusions:

• Passerini and Ugi MCRs are effective for synthesizing azirine-functionalized peptides.
• The synthesized compounds serve as precursors to a range of valuable heterocyclic structures.
• Azirine-containing depsipeptides represent a promising class of novel antibacterial agents against Gram-positive pathogens.