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

Abstract

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 μM. 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 μM. 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.

S-allylCysteine Ester/Caffeic Acid Amide Hybrids as Promising Antiprotozoal Candidates: Synthesis, Biological Evaluation and Molecular Modeling Studies

“…Several studies have shown that the presence of an α,β-unsaturated carbonyl group confers the necessary reactivity to inhibit cysteine-proteases, specially cruzipain and falcipain-2. The data regarding α,β-unsaturated compounds showed strong in vitro inhibitory potency against cruzipain from T. cruzi and FP-2 from P. Falciparum, making them highly efficient in blocking the enzymatic activity in protozoan systems (Machin, Kantsadi, Vakonakis, 2019;Tiwari et al, 2017;Borchhardt et al, 2010;Yang et al, 2009;Santos, Moreira, 2007;Kunakbaeva, Carrasco, Rozas, 2003;Hans-Hartwig, Tanja, 1997).…”

In vivo Antimalarial Activity of the Hydroalcoholic Extract of Kniphofia foliosa Hochst and Its Constituents

“…The two Plasmodium enzymes were plasmepsin II (PDB code 4cku) involved in haemoglobin metabolism by the parasite, and P. falciparum l-lactate dehydrogenase (pfLDH) (PDB code 1ldg) involved in glycolysis (or glucose metabolism of the parasite) [52,53,54]. There is a strong suggestion that haemoglobin digesting enzymes found in the food vacuole of the plasmodium and pfLDH are potential antimalarial chemotherapeutic targets for chloroquine and related aminoquionlones, anthraquinones and other oxidative phenolic compounds [55,56,57,58,59,60]. Besides, chloroquine has been found to bind to the cofactor (NADH) binding site of pfLDH acting as a competitive inhibitor [61].…”

In silico design of Plasmodium falciparum cysteine protease falcipain 2 inhibitors with favorable pharmacokinetic profile

“…The main strategy remains the increase of hydrophobic enzyme -ligand contact. 48 Due to the lack of quantitative accurate structural information about the pfFP2 active site subpockets efforts were oriented towards SAR studies of peptides and non peptidic scaffolds 49,50 but so far no integrated approach combining 3D-QSAR, PH4 and in silico screening has been reported and useful structural information is provided here.…”