Aryl piperazine and pyrrolidine as antimalarial agents. Synthesis and investigation of structure-activity relationships

Abstract

Piperazine and pyrrolidine derivatives were synthesized and evaluated for their capacity to inhibit the growth of Plasmodium falciparum chloroquine-resistant (FCR-3) strain in culture. The combined presence of a hydroxyl group, a propane chain and a fluor were shown to be crucial for the antiplasmodial activity. Five compounds of the aryl-alcohol series inhibited 50% of parasite growth at doses ≤ 10 µM. The most active compound 1-(4-fluoronaphthyl)-3-[4-(4-nitro-2-trifluoromethylphenyl)piperazin-1-yl]propan-1-ol was almost 20 to 40 times more active on Plasmodium falciparum (IC50: 0.5 µM) than on tumorogenic and non tumorogenic cells. Calculated physicochemical parameters showed a good potential for intestinal absorption, but due to difficulty in being solubilised prior to oral administration, it was weakly active against Plasmodium berghei infected mice (ED50: 35%). In silico molecular docking study and molecular electrostatic potential calculation revealed that this compound bound to the active site of Plasmodium plasmepsin II enzyme.