Wicht Kathryn J, Combrinck Jill M, Smith Peter J, Hunter Roger, Egan Timothy J
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Observatory 7925, South Africa.
ACS Med Chem Lett. 2017 Jan 24;8(2):201-205. doi: 10.1021/acsmedchemlett.6b00416. eCollection 2017 Feb 9.
In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against . Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.
在之前的一项研究中，针对β-血红素（合成疟色素）形成的抑制剂进行了基于靶点的筛选，并鉴定出一系列三芳基咪唑对……具有活性。在此，我们报告了该系列中三个苯环上具有不同取代基的衍生物的后续合成及测试情况。结果表明，A环上的2-羟基-1,3-二甲氧基取代模式是亚微摩尔级寄生虫活性所必需的。此外，细胞分级分离研究显示，细胞内可交换（游离）血红素出现异常大的剂量依赖性增加，这与β-血红素抑制衍生物的寄生虫存活率降低相关。
