In Vitro Antimalarial Evaluation of Piperidine- and Piperazine-Based Chalcones: Inhibition of Falcipain-2 and Plasmepsin II Hemoglobinases Activities from Plasmodium falciparum

Never-ending effort to develop new treatments for malaria, targeting the hemoglobin-degradation in the food vacuole of the parasite is of particular interest because it appears to be critical for the erythrocytic stage parasite development. The Plasmodium aspartic proteinases plasmepsins and cysteine proteases falcipains have been shown to be the major hemoglobin-degrading proteases and are proposed as the high priority drug targets by the World Health Organization for developing novel small molecules as inhibitors of hemoglobin degradation. In the present study, several piperidine and piperazine-based chalcones were assessed for anti-malarial activity against the chloroquine-susceptible P. falciparum 3D7 strain and inhibition of plasmepsin II and falcipain-2. Degradation of hemoglobin by falcipain-2 in the presence or absence of inhibitors was also demonstrated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The IC50 values of chalcones for cell growth inhibition were in the range of 1.60-153.51 mu M. IC50 values for cytotoxicity of selected chalcones against Michigan Cancer Foundation (MCF) 7 human breast adenocarcinoma cells were in the range of 8.46-15.64 mu M. Molecular docking studies revealed the binding orientation of these chalcones in the active sites of falcipain-2. Our results clearly depict the advantage of these chalcones as they kill P. falciparum malaria parasite in culture, most likely via inhibition of falcipain.