ANTIMALARIAL ACTIVITY OF MOLECULES INTERFERING WITH PLASMODIUM-FALCIPARUM PHOSPHOLIPID-METABOLISM - STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. Th ey were active over the 10(-3)-10(-8) M concentration range. A structu re-activity relationship study was carried out using autocorrelation v ectors as structural descriptors,and multidimensional analysis. Princi pal component analysis, ascending hierarchical classification, and ste pwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophil icity and electronegativity distribution in the molecular space essent ial. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the mole cules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quat ernary ammoniums salts whose nitrogen atom had only one long lipophili c chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by li near alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and subs titutions of nitrogen (aimed at increasing lipophilicity) were essenti al for optimal interactions. A crude topographic model of the ligand ( choline) binding site was thus drawn up.