Zakiah Mistika, Syarif Rul Afiyah, Mustofa Mustofa, Jumina Jumina, Fatmasari Nela, Sholikhah Eti Nurwening
Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Sekip Utara, Indonesia.
Faculty of Medicine, Universitas Tanjungpura, Pontianak 78115, Indonesia.
J Trop Med. 2021 Mar 31;2021:8866681. doi: 10.1155/2021/8866681. eCollection 2021.
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 -hematin , which is analog with hemozoin in . This study was conducted to evaluate the antiplasmodial activity of hydroxyxanthone derivative compounds on two strains of 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 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 (IC). 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 antiplasmodial activity on both 3D-7 and FCR-3 strains with IC values of 6.10 ± 2.01 and 6.76 ± 2.38 M, respectively. The 1,6,8-trihydroxyxanthone showed inhibition activity of heme polymerization with IC 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.
先前的研究表明，氧杂蒽具有抗疟原虫活性。合成了带有额外羟基的氧杂蒽，以增强其抗疟原虫活性。评估一种可开发成抗疟药物的化合物的策略之一是测试其抑制血红素聚合的机制。在酸性条件下，血红素可聚合成β-血红素，其与疟原虫中的疟色素类似。本研究旨在评估羟基氧杂蒽衍生物化合物对3D-7和FCR-3两种菌株的抗疟原虫活性，评估血红素聚合活性的抑制作用，并确定羟基氧杂蒽衍生物化合物的选择性。每种化合物的抗疟原虫活性在3D-7和FCR-3上进行测试，孵育72小时，采用显微镜法进行三次重复实验。表现出最佳抗疟原虫活性的化合物进行流式细胞术分析。使用体外血红素聚合抑制活性（HPIA）测定法进行血红素聚合抑制试验。抗疟原虫活性和血红素聚合抑制活性以50%抑制浓度（IC）表示。使用MTT测定法在Vero细胞系上测试体外细胞毒性，以确定其选择性指数。结果表明，在5-羟基氧杂蒽衍生物化合物中，1,6,8-三羟基氧杂蒽对3D-7和FCR-3菌株均具有最佳抗疟原虫活性，IC值分别为6.10±2.01和6.76±2.38μM。1,6,8-三羟基氧杂蒽表现出血红素聚合抑制活性，IC值为2.854mM，选择性指数为502.2-556.54，显示出高选择性。总之，在测试的5-羟基氧杂蒽衍生物中，1,6,8-三羟基氧杂蒽表现出最佳抗疟原虫活性，具有血红素聚合抑制活性和高选择性。
