Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-Heme Interaction and Multivariate Models

Artemisinins tested against W-2 strains of malaria falciparum are investigated with molecular electrostatic potential (MEP), in an attempt to identify key features of the compounds that are necessary for their activities, as well as to investigate likely interactions with the receptor in a biological process and to use that information to propose new molecules. In order to discover the best geometry involving the ligand-receptor complexes (heme) studied and help in the proposition of the new derivatives, molecular simulations of interactions between the most negative charged region around the peroxide and heme locates (the ones around the Fe2+ ion) were carried out. In addition, PCA (principal components analysis), HCA (hierarchical cluster analysis), SDA (stepwise discriminant analysis), and KNN (K-nearest neighbor) multivariate models were employed to investigate which descriptors are responsible for the classification between the higher and lower antimalarial activity of the compounds, and also this information was used to propose new potentially active molecules. The information accumulated in studies of MEP, molecular docking, and multivariate analysis supported the proposal of new structures with potential antimalarial activities. The multivariate models constructed were applied to the new structures and indicated numbers 19 and 20 as the most prominent for syntheses and biological assays.

In vivo antiplasmodial activity of extract and fractions of Trema orientalis in P.berghei-induced malaria in mice

Objective:To assess the in vivo antimalarial potential of various solvent extracts and fractions of Trema orientalis.Methods:In this study,the animal model of antimalarial activity was employed using Plasmodium berghei-induced mice.The crude methanol extract was fractionated using vacuum liquid chromatography in the order of increasing polarity using dichloromethane,ethylacetate and methanol.Percentages of parasitemia and clearance were used as indices for antiplasmodial activities.The full blood count was also assayed while the gas chromatography-mass spectrometer analysis of the most potent fraction was carried out to detect the active compounds presenting in it.Results:Dichloromethane fraction had the least percentage of parasitemia[(0.19±0.07)%]and the highest percentage of clearance[(91.74±8.38)%]at the highest dose used(200 mg/kg body weight)after day 7 relative to the artemisinin control which cleared the parasite after day 3.The ethylacetate fraction showed the least percentage of clearance[(70.52±5.64)%]at the highest dose used(200 mg/kg body weight)after day 7.Conclusions:The results obtained showed that purification enhanced the antiplasmodial activity of Trema orientalis in Plasmodium berghei-induced malaria in mice.The antiplasmodial activity of the dichloromethane is a strong indication that the fraction,if purified further,may contain drug candidates for the treatment of malaria in the nearest future.