Synthesis and Evaluation of Peptoid-Based Compound Libraries as Inhibitors of Parasite Metallo-Aminopeptidases.

Parasitic diseases are a worldwide health and socio-economical problem, especially due to increasing parasite resistance and frequent toxicity of commercial drugs. Parasite metallo-aminopeptidases are potential therapeutic targets, as they perform crucial biological functions during parasite development within the human host. Here, we describe the synthesis and biological evaluation of two libraries consisting of a total of 74 peptoid-based compounds. The synthetic approaches use a multicomponent reaction to install various diversity elements, and in library one, this is followed by subsequent coupling to α-amino acids to create further diversity within a peptoid-peptide hybrid skeleton. The libraries were evaluated against three metallo-aminopeptidases: PfA-M1 from Plasmodium falciparum, TcLAP from Trypanosoma cruzi, and LmLAP from Leishmania major, which allowed the discovery of moderate to potent inhibitors of each enzyme. Molecular docking studies were conducted to help understand the binding mode of the inhibitors with the enzymes, predicting the importance of hydrophobic interactions in the inhibition process.