Combined Approach of Backbone Amide Linking and On-Resin N‑Methylation for the Synthesis of Bioactive and Metabolically Stable Peptides

Rhabdopeptides
are a large class of nonribosomal peptides from
the bacteria Xenorhabdus and Photorhabdus with low micromolar activity against different protozoa, which are
the causative agents of several tropical diseases. The development
of a facile and flexible synthesis combining backbone amide linking
with on-resin peralkylation for the synthesis of permethylated rhabdopeptides
is described. This strategy allows the fast generation of permethylated
naturally occurring and artificial rhabdopeptides for a structure–activity
study. Furthermore, in vitro experiments revealed their superior properties
regarding their stability and passive membrane diffusion.