Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-ω-Diethylaminoalkoxyxanthone Series

Abstract

Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis--diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R 2 ‫؍‬ 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5-and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC 50 ) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 ؋ 10 5 and 9.02 ؋ 10 5 M ؊1 , respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.Malaria represents the most deadly parasitic human disease, despite countless efforts to eradicate or control it. Each year, it threatens roughly 40% of the world's population, infects over 200 million people, and claims 2 million lives-primarily children under 5 years of age (32, 36). To make matters worse, treatment of malaria is becoming increasingly more difficult due to the emergence of multidrug-resistant strains of Plasmodium falciparum, causative agent of the most severe form of the disease (32). As a result, there is a pressing need to develop novel antimalarial agents.The Plasmodium parasite infects erythrocytes and digests hemoglobin within an acidic food vacuole for salvage of critically needed amino acids (21). This proteolytic process results in the release of toxic heme, which is sequestered into an insoluble nontoxic substance known as hemozoin, or more commonly as "malaria pigment" (1,22,27). The classical antimalarial quinolines, quinine and chloroquine, are believed to act via complexation to heme in a manner that perturbs hemozoin formation (7,10,23,26,30).Hydroxyxanthones have been identified by us as a novel class of antimalarial compounds with activity against multidrug-resistant Plasmodium parasites (34,35). We have demonstrated that selected hydroxyxanthones form soluble complexes with heme and prevent the precipitation of heme in aqueous solution under the mildly acidic conditions of the digestive vacuole at pH 5.2 (14). In a recent study of the interaction between heme and 4,5-dihydroxyxanthone, a model that features carbonyl-iron coordination, -stacking of the coplanar aromatic molecules, and hydrogen bonding between the drug's hydroxyl substituents and the propionate side chains of heme was found to be consistent with the proton nuclear magnetic resona...

Anti-malarial activity of some xanthones isolated from the roots of Andrographis paniculata

“…Recently, xanthones have been identified as novel anti-malarial agents (Kelly et al, 2002;Ignatushchenko et al, 1997Ignatushchenko et al, , 2000. The antimalarial activity of xanthones exhibited by complexation to heme and inhibitition of hemozoin formation (Kelly et al, 2002).…”

Leishmanicidal and Cholinesterase Inhibiting Activities of Phenolic Compounds from Allanblackia monticola and Symphonia globulifera

“…Xanthones are known to show a wide range of biological activity such as antibacterial, antidiabetic, antiplasmodial, human cancer cell line growth inhibition, antihypertensive and vasorelaxing, cardiovascular protection, inhibition of HIV-1 reverse transcriptase and HIV-1 replication [9][10][11][12][13][14][15][16]. The leishmanicidal activity of several xanthones were reported previously [17], but to the best of our knowledge, there are no reports on leishmanicidal activity of benzophenones of the guttiferone type.…”

“Recycling” Classical Drugs for Malaria

“…94 Subsequently, Kelly et al gathered xanthones' heme-binding ability with the relevance of protonable amines in positions 3 or 6 of the xanthone ring to design compounds 61a and 61b ( Figure 30); the latter presented IC 50 values of 0.10 μM and 0.07 μM, respectively, against P. falciparum strain D6, being 1000-fold more active than dihydroxyxanthone (62, IC 50 > 60 μM). 95 Based on this knowledge, Winter et al pursued novel acridone derivatives which might enrol the ability to inhibit hemozoin formation with chemosensitizing properties. To this end, those authors started by synthesizing and evaluating 30 new derivatives of 2-methoxy-6-chloroacridone in order to build some SAR.…”