Multistage antiplasmodial activity of hydroxyethylamine compounds,in vitroandin vivoevaluations

Abstract

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains ofPlasmodiumspecies. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite's multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain ofP. falciparumblood-stage culture with 50% inhibitory concentrations (IC50) in the low micromolar range. The compounds' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC50values > 170 μM. Thein vivoefficacy was studied in mice infected withP. bergheiNK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound1with an IC50value of 1.89 μM. Mice infected withP. bergheisporozoites treated with compound1at 50 mg kg−1dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematicin silicostudies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.