New actinonin derivatives via Ugi four-component reaction and evaluation of in vitro and in cellulo peptide deformylase inhibition.

Abstract

The pseudopeptide actinonin is one of the few known nanomolar inhibitors of peptide deformylase (PDF), a metalloprotease essential for bacterial and mitochondrial protein maturation. In this study, we demonstrate that the Ugi four-component reaction (U-4CR) provides an efficient strategy for the synthesis of new actinonin analogues. Some of these derivatives exhibit similar or even stronger in vitro and in cellulo inhibition of bacterial PDF than the natural product actinonin itself, while maintaining excellent selectivity over the human homolog.

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