Structure/Antileishmanial Activity Relationship Study of Naphthoquinones and Dependency of the Mode of Action on the Substitution Patterns
Structure/Antileishmanial Activity Relationship Study of Naphthoquinones and Dependency of the Mode of Action on the Substitution Patterns
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DOI：
10.1055/s-0031-1280092
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发表时间：
2011-12-01
期刊：
影响因子：
2.7
通讯作者：
Kolodziej, Herbert
中科院分区：
文献类型：
--
作者：
Ali, Ahmad;Assimopoulou, Andreana Nikolaos;Kolodziej, Herbert
在体外测试了一系列萘醌对细胞外前鞭毛体和细胞内无鞭毛体硕大利什曼原虫GFP的活性。同时，评价化合物对骨髓源性巨噬细胞（BMM Phi）的细胞毒性作用，作为哺乳动物宿主细胞对照。大多数化合物明显抑制细胞外寄生虫的生长（IC（50）0.5 ~ 6 μ M）和L.主要GFP无鞭毛体（IC（50）1 - 7 μ M），与抗利什曼原虫药物阿替西菌素B（IC（50）分别为2.5和0.2 μ M）相比。一般而言，抗原虫活性和宿主细胞毒性似乎平行增加。显然，与未感染的细胞相比，对感染的宿主细胞的细胞毒性作用不太明显。关于测试的萘醌的结构/活性关系，本研究出现了一些有趣的结构特征。在母体1，4-萘醌的C-2位引入甲基或甲氧基略微增加了对临床相关无鞭毛体的抗利什曼原虫活性，而在该位置存在羟基官能团则显著降低了有效性。相反，在C-5和C-8的羟基化和二羟基取代显着增强抗原虫活性。类似地，当与取代的类似物相比时，如在紫草素/紫草素衍生物系列中所示的羰基官能团的侧链羟基的存在增加了活性。在所测试的一系列萘醌中，vaforhizin和isovaforhizin的二聚体混合物在体外对临床相关的细胞内无鞭毛体显示出最高的活性，IC（50）为1.1 μ M。IC（50）值大多在1-3 μ M范围内，紫草素/紫草素衍生物被证明具有类似的显著杀利什曼原虫的作用。测试的化合物中没有一种能够诱导已知在宿主对细胞内病原体的抗性中起关键作用的NO产生，不包括巨噬细胞中杀微生物机制的激活。的行动模式显然取决于取代模式，与亲电性的萘醌或氧化还原循环的效率。显然，在醌环中含氧的成员被证明是杀利什曼原虫时，与谷胱甘肽共孵育，而大多数剩余的化合物失去了活性。
A series of naphthoquinones was tested for activity against both extracellular promastigote and intracellular amastigote Leishmania major GFP in vitro. In parallel, the compounds were evaluated for cytotoxic effects against bone marrow-derived macrophages (BMM Phi) as a mammalian host cell control. Most of the compounds noticeably inhibited the growth of extracellular parasites (IC(50) 0.5 to 6 mu M) and the intracellular survival of L. major GFP amastigotes (IC(50) 1 to 7 mu M) when compared with the antileishmanial drug amphotericin B (IC(50) of 2.5 and 0.2 mu M, respectively). In general, antiprotozoal activity and host cell cytotoxicity seemed to increase in parallel. Conspicuously, the cytotoxic effect was less pronounced on infected host cells when compared with that on noninfected cells. Concerning structure/activity relationships for the tested naphthoquinones, some interesting structural features emerged from this study. Introduction of a methyl or methoxyl group at C-2 of the parent 1,4-naphthoquinone slightly increased the antileishmanial activity against clinically relevant amastigotes, while the presence of a hydroxyl function in this position dramatically reduced the effectiveness. In contrast, hydroxylation at C-5 and dihydroxy substitution at C-5 and C-8 significantly enhanced the antiprotozoal activity. Similarly, the presence of a side chain hydroxyl group peri to a carbonyl function as represented in the series of shikonin/alkannin derivatives increased the activity when compared with substituted analogs. Within the series of naphthoquinones tested, the dimeric mixture of vaforhizin and isovaforhizin showed the highest activity in vitro against the clinically relevant intracellular amastigote with an IC(50) of 1.1 mu M. With IC(50) values mostly in the range of 1-3 mu M, the shikonin/alkannin derivatives proved to be similarly considerably leishmanicidal. None of the compounds tested was capable to induce NO production known to play a crucial role in the host resistance against intracellular pathogens, excluding activation of microbicidal mechanisms in macrophages. The mode of action apparently depended on the substitution pattern, associated with the electrophilicity of the naphthoquinone or the efficiency of redox cycling. Conspicuously, members oxygenated in the quinone ring proved to be leishmanicidal when coincubated with glutathione, while the majority of the remaining compounds lost activity.