In vivo evaluation of isolated triterpenes and semi-synthetic derivatives as antimalarial agents

The triterpenes balsaminoside B (1) and karavilagenin C (2) were isolated from the African medicinal plant Momordica balsamina L. Karavoates B (3) and D (4) were synthesized by diacylation of 2 with acetic and propionic anhydrides, respectively. In previous work, derivatives 3 and 4 exhibited submicromolar median inhibitory concentrations (IC50) in vitro against Plasmodium falciparum Welch (human malaria parasite) strains 20 to 25 times lower than those of natural product 2. The main objective of the present study was to explore structure-in vivo antimalarial activity relationships (SAR) for compounds 1-4 in Plasmodium berghei Vincke and Lips NK65-infected mice in the 4 day suppressive test. Semi-synthetic derivatives 3 and 4 exhibited greater in vivo antimalarial activity than isolates 1 and 2. Orally and subcutaneously administered karavoate B exhibited the greatest in vivo antimalarial activity (55.2-58.1% maximal suppression of parasitemia at doses of 50 mg kg-1 day-1). Diacylation of natural isolate 2 with short chain carboxylic acid moieties yielded derivatives with enhanced maximal in vivo parasitemia suppression for both routes of administration. Maximal in vivo parasite suppression by diacetyl derivative 3 was roughly double that of natural precursor 2. © 2015 Published by Elsevier Masson SAS

In vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives

4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated from Piper peltatum roots. O-Acylation or O-alkylation of compound 1 provides derivatives exhibiting improved stability and significant in vitro antiplasmodial activity. The aim of this work was to study the in vitro inhibition of hemozoin formation, inhibition of isoprenoid biosynthesis in Plasmodium falciparum cultures, and in vivo antimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibited in vitro hemozoin formation by up to 50%. In metabolic labeling studies using [1-(n)-3H]geranylgeranyl pyrophosphate, diester 2 significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone 8, menaquinone 4, and dolichol 12 in cultures of P. falciparum 3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol 12. P. falciparum in vitro protein synthesis was not affected by compounds 2 or 3. At oral doses of 50 mg per kg of body weight per day, compound 2 suppressed Plasmodium berghei NK65 in infected BALB/c mice by 44%. This in vivo result for derivative 2 represents marked improvement over that obtained previously for natural product 1. Compound 2 was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasma in vitro. However, it was detected after in vitro contact 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. Copyright © 2015, American Society for Microbiology. All Rights Reserved

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived