Tasdemir Deniz, Kaiser Marcel, Brun Reto, Yardley Vanessa, Schmidt Thomas J, Tosun Fatma, Rüedi Peter
Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Antimicrob Agents Chemother. 2006 Apr;50(4):1352-64. doi: 10.1128/AAC.50.4.1352-1364.2006.
Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC50], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3',4'-tetrahydroxyflavone (IC50s, 0.5 microg/ml) and catechol (IC50, 0.8 microg/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 microg/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC50s of 0.6, 0.7, 0.8, and 1.0 microg/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents.
锥虫病和利什曼病是影响非洲、亚洲和南美洲数百万人的重要寄生虫病。在先前的一项研究中，我们从一种土耳其植物中鉴定出几种黄酮糖苷作为抗原生动物成分。在此，我们调查了一大组黄酮苷元、糖苷以及一组其他具有酚类和苯丙素类性质的相关化合物对布氏罗得西亚锥虫、克氏锥虫和杜氏利什曼原虫的体外活性。还评估了100多种化合物对哺乳动物L6细胞的细胞毒性，并将其与它们的抗寄生虫活性进行比较。在小鼠模型中对几种化合物进行了体内抗利什曼和抗锥虫疗效的研究。总体而言，7,8 - 二羟基黄酮对布氏罗得西亚锥虫的体外杀锥虫活性最佳（50%抑制浓度[IC50]，68 ng/ml），其次是3 - 羟基黄酮、鼠李素、7,8,3',4' - 四羟基黄酮（IC50s，0.5 μg/ml）和儿茶酚（IC50，0.8 μg/ml）。对克氏锥虫的活性中等，只有白杨素二甲醚和3 - 羟基大豆苷元的IC50小于5.0 μg/ml。大多数测试的代谢物具有显著的杀利什曼原虫潜力。非瑟酮、3 - 羟基黄酮、木犀草素和槲皮素最为有效，IC50分别为0.6、0.7、0.8和1.0 μg/ml。7,8 - 二羟基黄酮和槲皮素似乎能改善小鼠模型中的寄生虫感染。一般来说，测试化合物在体外和体内均无细胞毒性。通过筛选大量黄酮类化合物及其类似物，我们能够确定一些关于构效关系的一般趋势，但通过两种不同方法都无法为任何生物活性绘制清晰详细的定量构效关系。然而，我们的结果有助于指导合理设计7,8 - 二羟基黄酮和槲皮素衍生物作为有效且高效的抗原生动物药物。
