Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Eur J Med Chem. 2013 Aug;66:450-65. doi: 10.1016/j.ejmech.2013.05.007. Epub 2013 May 16.
A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
针对布鲁氏锥虫的全生物体高通量筛选了大约 87000 种化合物，最近发现了几类新型化合物，对该生物体具有低微摩尔的活性，且对哺乳动物细胞没有明显的细胞毒性。在此，我们报告了其中一类命中化合物（3-（恶唑并[4,5-b]吡啶-2-基）苯胺）的构效关系（SAR）研究。揭示了明显的 SAR，我们最有效的化合物（5）对引起人类疾病的冈比亚锥虫株 T.b. rhodesiense 的 IC₅₀为 91 nM，对 L6 哺乳动物细胞系的毒性低 700 多倍。该系列中的许多化合物都具有有吸引力的物理化学性质。对于最有效的代表化合物，我们表明在未来的优化过程中，溶解度和代谢稳定性是需要针对的关键参数。
