Semisynthesis of Lupane Derivatives, their In Vitro Evaluation Against Plasmodium falciparum FCR-3 Strain and an In Silico Study on PfATP6 Protein

The escalating issue of malaria, including the parasite's resistance to the most effective antimalarial drugs, underscores the significance of discovering a novel antimalarial agent. Extensive research has been conducted on the phytochemicals, including triterpenoids, due to their efficacy in combating malaria. Therefore, in this study, we describe the semisynthesis and characterization of triterpenoids of lupane derivatives by simple modification at the C-3 position, including the evaluation of their efficacy, both in vitro against the Plasmodium falciparum FCR-3 strain and in silico molecular docking simulations targeting the PfATP6 protein. As a result, the structural modification at the C-3 position with 2-furoyl moiety (2b) shows a moderate activity with IC50 = 20.8 ± 0.7 μM, compared to its precursor lupeol (2), which shows a weak activity with IC50 = 122.1 ± 0.3 μM (positive control chloroquine; IC50 = 15.0 ± 0.1 μM). Molecular docking demonstrated a good interaction between 2b and the active site of PfATP6 protein, with a binding energy of - 8.0 ± 0.0 kcal mol-1. The 2-furoyl ring in 2b shows the binding interaction with the Asn1039 residue via hydrogen bonds. Therefore, compound 2b is identified as a promising candidate as a lead compound for further antiplasmodial studies. conclusion: Based on the results of the antiplasmodial activity, derivative 2b exhibited the strongest potency among the compounds tested and showed moderate activity with an IC50 value of 20.8 μM. Docking analysis with AutoDock Vina on the parasite protein PfATP6 with the most potent ligand 2b (ΔG : -8.0 kcal mol-1; Ki : 1.37 μM) revealed that the 2-furoyl substituent formed more bonds and developed numerous hydrophobic interactions, including van der Waals, showing strong intercalations with the residues at the active sites of this protein receptor. This study also highlights the effects of a simple structural modification at C-3 of precursor 2 on the bioactive properties of the 2a-2e analogs, which enhanced their antiplasmodial results in contrast to the precursor. The findings of this research may contribute to the design and development of lupane derivatives as potential antiplasmodial lead compounds.