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Nineteen 10-substitued deoxoartemisinin derivatives and artemisinin with activity against D-6 strains of malarial falciparum designated as Sierra Leone are studied. We use molecular electrostatic potential maps in an attempt to identify key structural features of the artemisinins that are necessary for their activities and molecular docking to investigate the interaction with the molecular receptor (heme). Chemometric modeling: Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA), K-Nearest Neighbor (KNN), Soft Independent Modeling of Class Analogy (SIMCA) and Stepwise Discriminant Analysis (SDA) are employed to reduce dimensionality and investigate which subset of descriptors are responsible for the classification between more active (MA) and less active (LA) artemisinins. The PCA, HCA, KNN, SIMCA and SDA studies showed that the descriptors LUMO (Lowest Unoccupied Molecular Orbital) energy, DFeO1 (Distance between the O 1 atom from ligand and iron atom from heme), X1A (Average Connectivity Index Chi-1) and Mor15u (Molecular Representation of Structure Based on Electron Diffraction) code of signal 15, unweighted, are responsible for separating the artemisinins according to their degree of antimalarial activity. The prediction study was done with a new set of eight artemisinins by using the chemometric methods and five of them were predicted as active against D-6 strains of falciparum malaria. In order to verify if the key structural features that are necessary for their antimalarial activities were investigated for the interaction with the heme, we also carried out calculations of the molecular electrostatic potential (MEP) and molecular docking. MEP maps and molecular docking were analyzed for more active compounds of the prediction set.

The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain-2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine-resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs.

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