ABSTRACT
Sixteen triterpenoids (1-16), previously isolated from the aerial parts of the African medicinal plant Momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of Plasmodium berghei, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luccon. Toxicity of compounds (1-16) was assessed on the same cell line through the fluorescence measurement of cell confluency. The highest activity was displayed by a derivative bearing two acetyl residues, karavoate B (7), which led to a dose-dependent decrease in the P. berghei infection rate, exhibiting a very significant activity at the lowest concentration employed (1 µM) and no toxicity towards the Huh-7 cells. It is noteworthy that, in previous studies, this compound was found to be a strong inhibitor of blood-stages of Plasmodium falciparum, thus displaying a dual-stage antimalarial activity.
Subject(s)
Antimalarials/chemistry , Momordica/chemistry , Triterpenes/chemistry , Antimalarials/isolation & purification , Antimalarials/pharmacology , Cell Line , Cell Survival/drug effects , Humans , Momordica/metabolism , Plant Components, Aerial/chemistry , Plant Components, Aerial/metabolism , Plants, Medicinal/chemistry , Plants, Medicinal/metabolism , Plasmodium falciparum/drug effects , Triterpenes/isolation & purification , Triterpenes/pharmacologyABSTRACT
Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host's liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite's replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite's mitochondrial bc(1) complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound.