Histidinal‐Based Potent Antimalarial Agents

Abstract

AbstractHerein 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 compounds8 g,8 h, and15exhibited 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 compounds8 g,8 h, and15interact 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 compound8 gand 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.