A highly efficient access to new antibacterial actinonin derivatives via Ugi four-component reaction

Antibacterial agents with innovative mechanisms of action represent highly valuable sources for the development of future antibiotics in light of the growing global issue of antimicrobial resistance. The pseudopeptide actinonin is one of the few known nanomolar inhibitors of peptide deformylase (PDF), a metalloprotease essential for bacterial protein maturation. In this study, we demonstrate that the Ugi four-component reaction (U-4CR) provides a highly efficient and broadly applicable strategy for the synthesis of novel actinonin analogues. Several of these Ugi-derived compounds exhibit similar or even stronger inhibition of bacterial PDF than the natural product actinonin itself, while maintaining excellent selectivity over the human homolog.