Antimalarial activity of compounds interfering with Plasmodium falciparum phospholipid metabolism: Comparison between mono- and bisquaternary ammonium salts

On the basis of a previous structure-activity relationship study, we identi fied some essential parameters, e.g. electronegativity and lipophilicity, r equired for polar head analogues to inhibit Plasmodium falciparum phospholi pid metabolism, leading to parasite death. To improve the in vitro antimala rial activity, 36 cationic choline analogues consisting of mono-, bis-, and triquaternary ammonium salts with distinct substituents of increasing lipo philicity were synthesized. For monoquaternary ammonium salts, an increase in the lipophilicity around nitrogen was beneficial for antimalarial activi ty: IC50 decreased by 1 order of magnitude from trimethyl to tripropyl subs tituents. Irrespective of the polar head substitution (methyl, ethyl, hydro xyethyl, pyrrolidinium), increasing the alkyl chain length from 6 to 12 met hylene groups always led to increased activity. The highest activity was ob tained for the N,N,N-tripropyl-N-dodecyl substitution of nitrogen (IC50 33 nM). Beyond 12 methylene groups, the antimalarial activities of the compoun ds decreased slightly. The structural requirements for bisquaternary ammoni um salts in antimalarial activity were very similar to those of monoquatern ary ammonium salts, i.e, polar head steric hindrance and lipophilicity arou nd nitrogen (methyl, hydroxyethyl, ethyl, pyrrolidinium, etc.). In contrast , with bisquaternary ammonium salts, increasing the lipophilicity of the al kyl chain between the two nitrogen atoms (from 5 to 21 methylene groups) co nstantly and dramatically increased the activity. Most of these duplicated molecules had activity around 1 nM, and the most lipophilic compound synthe sized exhibited an IC50 as low as 3 pM (21 methylene groups). Globally, thi s oriented synthesis produced 28 compounds out of 36 with an IC50 lower tha n 1 mu M, and 9 of them had an IC50 in the nanomolar range, with 1 compound in the picomolar range. This indicates that developing a pharmacological m odel for antimalarial compounds through choline analogues is a promising st rategy.