Histidinal‐Based Potent Antimalarial Agents

Abstract

Herein we report the synthesis and evaluation of peptide‐histidinal conjugated drug scaffolds, which have the potential to target the hemoglobin‐degrading proteases falcipain‐2/3 from the human malaria parasite. Scaffolds with various substitutions were tested for antimalarial activity, and compounds 8 g, 8 h, and 15 exhibited EC50 values of ∼0.018 μM, ∼0.069 μM, and ∼0.02 μM, respectively. Structure‐based docking studies on falcipain‐2/3 proteases (PDB:2GHU and PDB:3BWK) revealed that compounds 8 g, 8 h, and 15 interact strongly with binding sites of falcipain‐2/3 in a substrate‐like manner. In silico ADME studies revealed that the molecules of interest showed no or minimal violations of drug‐likeness parameters. Further, phenotypic assays revealed that compound 8 g and its biotinylated version inhibit hemoglobin degradation in the parasite food vacuole. The identification of falcipain‐2/3 targeting potent inhibitors of the malaria parasite can serve as a starting point for the development of lead compounds as future antimalarial drug candidates.