Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
Eur J Med Chem. 2012 Sep;55:449-54. doi: 10.1016/j.ejmech.2012.06.058. Epub 2012 Jul 14.
The effects of reducing the molecular weight of the antileishmanial compound DB766 on DNA binding affinity, antileishmanial activity and cytotoxicity are reported. The bis-arylimidamides were prepared by the coupling of aryl S-(2-naphthylmethyl)thioimidates with the corresponding amines. Specifically, we have prepared new series of bis-arylimidamides which include 3a, 3b, 6, 9a, 9b, 9c, 13, and 18. Three compounds 9a, 9c, and 18 bind to DNA with similar or moderately lower affinity to that of DB766, the rest of these compounds either show quite weak binding or no binding at all to DNA. Compounds 9a, 9c, and 13 were the most active against Leishmania amazonensis showing IC(50) values of less than 1 μM, so they were screened against intracellular Leishmania donovani, showing outstanding activity with IC(50) values of 25-79 nM. Despite exhibiting little in vitro cytotoxicity these three compounds were quite toxic to mice.
报道了降低抗利什曼原虫化合物 DB766 分子量对其与 DNA 结合亲和力、抗利什曼原虫活性和细胞毒性的影响。双芳基脒类化合物是通过芳基 S-（2-萘甲基）硫代亚氨基与相应的胺偶联制备的。具体而言，我们已经制备了新的一系列双芳基脒类化合物，包括 3a、3b、6、9a、9b、9c、13 和 18。三种化合物 9a、9c 和 18 与 DNA 的结合亲和力与 DB766 相似或略低，其余化合物与 DNA 的结合能力相当弱或根本没有结合。化合物 9a、9c 和 13 对亚马逊利什曼原虫的活性最高，IC50 值低于 1 μM，因此对细胞内利什曼原虫进行了筛选，IC50 值为 25-79 nM，活性突出。尽管这三种化合物在体外显示出很小的细胞毒性，但对小鼠却有相当的毒性。
