In VivoAntimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

Abstract

ABSTRACT4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated fromPiper peltatumroots.O-Acylation orO-alkylation of compound1provides derivatives exhibiting improved stability and significantin vitroantiplasmodial activity. The aim of this work was to study thein vitroinhibition of hemozoin formation, inhibition of isoprenoid biosynthesis inPlasmodium falciparumcultures, andin vivoantimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibitedin vitrohemozoin formation by up to 50%. In metabolic labeling studies using [1-(n)-3H]geranylgeranyl pyrophosphate, diester2significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone8, menaquinone4, and dolichol12in cultures ofP. falciparum3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol12.P. falciparumin vitroprotein synthesis was not affected by compounds2or3. At oral doses of 50 mg per kg of body weight per day, compound2suppressedPlasmodium bergheiNK65 in infected BALB/c mice by 44%. Thisin vivoresult for derivative2represents marked improvement over that obtained previously for natural product1. Compound2was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasmain vitro. However, it was detected afterin vitrocontact with human blood or blood plasma. Derivatives of 4-nerolidylcatechol exhibit parasite-specific modes of action, such as inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation, and they therefore merit further investigation for their antimalarial potential.