Gordhan Heeren M, Patrick Stephen L, Swasy Maria I, Hackler Amber L, Anayee Mark, Golden Jennifer E, Morris James C, Whitehead Daniel C
Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA.
Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 249 Life Sciences Building, Clemson University, Clemson, SC 29634, USA.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):537-541. doi: 10.1016/j.bmcl.2016.12.021. Epub 2016 Dec 10.
Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high throughput screen revealed ebselen (EbSe), and its sulfur analog, EbS, to be potent in vitro inhibitors of the T. brucei hexokinase 1 (TbHK1). These molecules also exhibited potent trypanocidal activity in vivo. In this manuscript, we synthesized a series of sixteen EbSe and EbS derivatives bearing electron-withdrawing carboxylic acid and methyl ester functional groups, and evaluated the influence of these substituents on the biological efficacy of the parent scaffold. With the exception of one methyl ester derivative, these modifications ablated or blunted the potent TbHK1 inhibition of the parent scaffold. Nonetheless, a few of the methyl ester derivatives still exhibited trypanocidal effects with single-digit micromolar or high nanomolar EC values.
人类非洲锥虫病是撒哈拉以南非洲地区的一种疾病，数百万人面临感染该病的风险。这种疾病通常被称为非洲昏睡病，由真核病原体布氏锥虫感染引起。此前，一项基于靶点的高通量筛选显示，依布硒仑（EbSe）及其硫类似物EbS是布氏锥虫己糖激酶1（TbHK1）的有效体外抑制剂。这些分子在体内也表现出强大的杀锥虫活性。在本论文中，我们合成了一系列16种带有吸电子羧酸和甲酯官能团的EbSe和EbS衍生物，并评估了这些取代基对母体支架生物活性的影响。除了一种甲酯衍生物外，这些修饰消除或削弱了母体支架对TbHK1的有效抑制作用。尽管如此，一些甲酯衍生物仍表现出杀锥虫作用，其半数有效浓度（EC）值在个位数微摩尔或高纳摩尔范围内。
