D-Proline-based peptidomimetic inhibitors of anthrax lethal factor

In this work we reported the generation of D-proline-derived hydroxamic acids as inhibitors of anthrax lethal factor (LF), taking advantage of a pyrrolidine ring as the central scaffold and a hydroxamate group as the Zn2+ chelating agent. The introduction of two hydrophobic groups addressing the S10 subsite and a long substrate-binding groove was conceived by overlapping the bioactive conformations of two reported LF inhibitors. Micromolar affinity of compound 38 suggested cis-3-substituted-1-sulfonamido-D-proline hydroxamic acids as a promising class of peptidomimetic inhibitors for developing novel LF inhibitors.