International Journal for Parasitology: Drugs and Drug Resistance ( IF 4 ) Pub Date : 2020-05-24 , DOI: 10.1016/j.ijpddr.2020.05.003 Phanankosi Moyo 1 , William Shamburger 2 , Mariëtte E van der Watt 1 , Janette Reader 1 , Ana Carolina C de Sousa 3 , Timothy J Egan 4 , Vinesh J Maharaj 5 , Gerhard Bringmann 6 , Lyn-Marie Birkholtz 1
The discovery and development of multistage antimalarial drugs targeting intra-erythrocytic asexual and sexual Plasmodium falciparum parasites is of utmost importance to achieve the ambitious goal of malaria elimination. Here, we report the validation of naphthylisoquinoline (NIQ) alkaloids and their synthetic analogues as multistage active antimalarial drug candidates. A total of 30 compounds were tested, of which 17 exhibited IC50 values <1 μM against drug-sensitive P. falciparum parasites (NF54 strain); 15 of these retained activity against a panel of drug-resistant strains. These compounds showed low in vitro cytotoxicity against HepG2 cells, with selectivity indices of >10. The tested compounds showed activity in vitro against both early- and late-stage P. falciparum gametocytes while blocking male gamete formation (>70% inhibition of exflagellation at 2 μM). Additionally, five selected compounds were found to have good solubility (≥170 μM in PBS at pH 6.5), while metabolic stability towards human, mouse, and rat microsomes ranged from >90% to >7% after 30 min. Dioncophylline C (2a) emerged as a front runner from the study, displaying activity against both asexual parasites and gametocytes, a lack of cross-resistance to chloroquine, good solubility, and microsomal stability. Overall, this is the first report on the multistage activity of NIQs and their synthetic analogues including gametocytocidal and gametocidal effects induced by this class of compounds.
中文翻译:
萘基异喹啉生物碱,经验证可作为热门的多级抗疟原虫天然产物。
针对红细胞内无性和性恶性疟原虫寄生虫的多阶段抗疟药的发现和开发对于实现消除疟疾这一宏伟目标至关重要。在这里,我们报告验证萘异喹啉(NIQ)生物碱及其合成类似物作为多阶段活性抗疟药候选药物的有效性。总共测试了30种化合物,其中17种对药物敏感性恶性疟原虫寄生虫(NF54株)的IC 50值<1μM 。这些中的15种保留了针对一组耐药菌株的活性。这些化合物对HepG2细胞的体外细胞毒性较低,选择性指数> 10。被测化合物显示出活性在体外对抗早期和晚期恶性疟原虫配子细胞,同时阻断雄性配子的形成(在2μM时抑制70%的鞭毛形成)。此外,发现五种选定的化合物具有良好的溶解性(在pH 6.5的PBS中≥170μM),而对人,小鼠和大鼠微粒体的代谢稳定性在30分钟后范围从> 90%到> 7%。Dioncophylline C(2a)从研究中脱颖而出,显示出对无性寄生虫和配子细胞的活性,对氯喹的交叉抗性缺乏,良好的溶解性和微粒体稳定性。总体而言,这是有关NIQ及其合成类似物的多阶段活性的首份报告,包括此类化合物引起的杀细胞杀灭作用和杀螨作用。