Abstract.
Artemisinin derivatives with antimalarial activity against Plasmodium falciparum resistant to mefloquine are designed with the aid of Quantum Chemical and Partial Least Squares Methods. The PLS model with three principal components explaining 89.55% of total variance, Q² = 0.83 and R² = 0.92 was obtained for 14/5 molecules in the training/external validation set. The most important descriptors for the design of the model were one level above the lowest unoccupied molecular orbital energy (LUMO+1), atomic charges in atoms C9 and C11 (Q₉) and (Q₁₁) respectively, the maximum number of hydrogen atoms that might make contact with heme (NH) and RDF030m (a radial distribution function centered at 3.0 Å interatomic distance and weighted by atomic masses). From a set of ten proposed artemisinin derivatives, a new compound (26), was predicted with antimalarial activity higher than the compounds reported in literature. Molecular graphics and modeling supported the PLS results and revealed heme-ligand and protein-ligand stereoelectronic relationships as important for antimalarial activity. The most active 26 and 27 in the prediction set possess substituents at C9 able to extend to hemoglobin exterior, what determines the high activity of these compounds.

Keywords.
Artemisinin derivatives; Antimalarial activity; Plasmodium falciparum; Quantum Chemical Methods; PLS; QSAR; Molecular Graphics and Modeling.

Keywords Plus.
Crystal Structures; Dihydroartemisinin Derivatives; Pharmacological Analysis; Qinghaosu Artemisinin; Molecular Structure; Organic Molecules; Agent  Artemisinin; Analogs; Drugs; QSAR.