Abstract
The previous study showed that xanthone had antiplasmodial activity. Xanthone, with additional hydroxyl groups, was synthesized to increase its antiplasmodial activity. One of the strategies to evaluate a compound that can be developed into an antimalarial drug is by testing its mechanism in inhibiting heme polymerization. In acidic condition, hematin can be polymerized to β-hematin in vitro, which is analog with hemozoin in Plasmodium. This study was conducted to evaluate the antiplasmodial activity of hydroxyxanthone derivative compounds on two strains of Plasmodium falciparum 3D-7 and FCR-3, to assess inhibition of heme polymerization activity and determine the selectivity of hydroxyxanthone derivative compounds. The antiplasmodial activity of each compound was tested on Plasmodium falciparum 3D-7 and FCR-3 with 72 hours incubation period, triplicated in three replications with the microscopic method. The compound that showed the best antiplasmodial activity underwent flow cytometry assay. Heme polymerization inhibition test was performed using the in vitro heme polymerization inhibition activity (HPIA) assay. The antiplasmodial activity and heme polymerization inhibition activity were expressed as the 50% inhibitory concentration (IC50). In vitro cytotoxicity was tested using the MTT assay method on Vero cell lines to determine its selectivity index. The results showed that among 5-hydroxyxanthone derivative compounds, the 1,6,8-trihydroxyxanthone had the best in vitro antiplasmodial activity on both 3D-7 and FCR-3 Plasmodium falciparum strains with IC50 values of 6.10 ± 2.01 and 6.76 ± 2.38 μM, respectively. The 1,6,8-trihydroxyxanthone showed inhibition activity of heme polymerization with IC50 value of 2.854 mM and showed the high selectivity with selectivity index of 502.2–556.54. In conclusion, among 5-hydroxyxanthone derivatives tested, the 1,6,8-trihydroxyxantone showed the best antiplasmodial activity and has heme polymerization inhibition activity and high selectivity.
Highlights
Malaria is an infectious disease caused by a Plasmodium parasite transmitted through female Anopheles mosquito bites [1]. ere are five types of Plasmodium species that cause malaria in humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi
Plasmodium Culture. e test of antiplasmodial activity began with the culture of P. falciparum 3D-7 and FCR-3 using the modified Trager and Jensen method [15]. e plasmodium was cultured in human O red blood cells diluted to 3% haematocrit in RPMI 1640 medium complemented with 10% human O serum. e medium was made by adding 10.43 g of powder RPMI 1640, 6 g HEPES, 2 g NaHCO3, 25 mg gentamycin, and sterile distilled water up to 1 L. e medium pH was adjusted so that it reached ±7.2
In Vitro Antiplasmodial Activity Assay. e increasing concentrations of testing compounds showed increasing the percentage of Plasmodium growth inhibition. e percentages of Plasmodium growth inhibition of hydroxyxanthone derivatives and chloroquine on P. falciparum 3D-7 and FCR-3 are presented in Table 1. e inhibitory concentration of 50% (IC50) values of hydroxyxanthone derivatives on P. falciparum 3D-7 and FCR-3 are presented in Table 2. e lowest IC50 value of the hydroxyxanthone derivative compound on P. falciparum 3D-7 6.10 ± 2.01 μM was found in HX1
Summary
Malaria is an infectious disease caused by a Plasmodium parasite transmitted through female Anopheles mosquito bites [1]. ere are five types of Plasmodium species that cause malaria in humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Plasmodium falciparum (P. falciparum) is a cause of malaria with severe symptoms which can lead to death [2]. One of the mechanisms of antimalarials is inhibiting the polymerization of heme. E polymerization of the heme is the process of changing free heme to hemozoin. One of the drugs that have a mechanism of action inhibiting the polymerization of heme is chloroquine [3, 4]. E formation of chloroquine and heme complexes can inhibit hemozoin formation [5]. E free heme is polymerized by the Plasmodium into nontoxic. Hemozoin has a similar structure to β-hematin, while heme is similar to hematin. Erefore, by assessing this process, a compound can be developed into an antimalarial drug using the mechanism of action of heme polymerization. In vitro hematin can be polymerized into β-hematin in the acidic conditions, which has the same properties as existing hemozoin in the Plasmodium [6]
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