Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Abstract

Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ϳ10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

Antiplasmodial natural products: an update

“…This suggests a different mechanism of action from other anti-malarial drugs, such as atovaquone, that target parasite mitochondria. The cytotoxicity of the compounds against HEK293 cells was in the µM range, making them selectively toxic to the parasite at the active concentration (SI > 100) [230]. A tetrahydroxanthone dimer, dicerandrol D ( 370 ), from the endophytic fungus Diaporthe sp.…”

“…Natural products have also modulated their parasite killing effect by disrupting the haem detoxification systems as well as induction of oxidative stress and lipid peroxidation in the parasite (Table 1). Some natural products have also been reported to mediate antiplasmodial activity by inducing morphological and ultrastructural changes that are detrimental to parasite viability [230, 289].…”

Study on Synthesis and Biological Evaluation of 3-Aryl Substituted Xanthone Derivatives as Novel and Potent Tyrosinase Inhibitors

“…Xanthones are a class of oxygen-containing heterocycles with γ-pyran moiety condensed with two benzene rings, which are widely distributed in nature. 18) In recent years, xanthone derivatives have been received considerable attention in the field of medicinal chemistry because of their diversely biological functions, 20,21) such as anti-oxidant, 22) anti-hypertensive, 23) anti-convulsant, 24) anti-cholinesterase, 25) anti-malarial, 26) antimicrobial, 27) anti-inflammatory, 28) and anti-cancer activities. 29) Besides, they also served as the effective inhibitors of several enzymes like α-glycosidase, 30,31) topoisomerase, 32) proteinkinase, 33) aromatase.…”

Synergistic Effect of Garcinia Mangostana Combined With Chlorhexidine on Acanthamoeba Triangularis Trophozoites and Cysts

“…The synthetic Caged Garcinia xanthones (CGXs) exhibit anti-malarial activity against P. falciparum with low toxicity. It was reported that CGXs treatment affect malaria parasites relating to morphological changes, signi cant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation [21]. Benzophenone (isoxanthochymol) was isolated from the roots of G. polyantha which showed strong chemosuppressive activity of parasitic growth found in P. falciparum [22].…”