Novel Antiplasmodial Compounds Leveraged with Multistage Potency against the Parasite Plasmodium falciparum: In Vitro and In Vivo Evaluations and Pharmacokinetic Studies

摘要

Hydroxyethylamine (HEA)-based novel compounds were synthesized and their activity against Plasmodium falciparum 3D7 was assessed, identifying a few hits without any apparent toxicity. Hits 5c and 5d also exhibited activity against resistant field strains, PfRKL-9 and PfC580Y. A single dos; 50 mg/Kg, of hits administered to the rodent parasite Plasmodium berghei ANKA exhibited up to 70% reduction in the parasite load. Compound 5d tested in combination with artesunate produced an additional antiparasitic effect with a prolonged survival period. Additionally, compound Sd showed 50% inhibition against hepatic P. berghei infection at 1.56 +/- 0.56 mu M concentration. This compound also considerably delayed the progression of transmission stages, ookinete and oocyst. Furthermore, the toxicity of Sd assessed in mice supported the normal liver and kidney functions. Altogether, HEA analogues (5a-m), particularly Sd, are nontoxic multistage antiplasmodial agents with therapeutic and transmission-blocking efficacy, along with favorable preliminary pharmacokinetic properties.