Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
J Med Chem. 2012 Mar 22;55(6):2606-22. doi: 10.1021/jm2014259. Epub 2012 Mar 6.
A series of 73 bisphosphonium salts and 10 monophosphonium salt derivatives were synthesized and tested in vitro against several wild type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48). More than half of the compounds tested showed a submicromolar EC(50) against these parasites. The compounds did not display any cross-resistance to existing diamidine therapies, such as pentamidine. In most cases, the compounds displayed a good selectivity index versus human cell lines. None of the known T. b. brucei drug transporters were required for trypanocidal activity, although some of the bisphosphonium compounds inhibited the low affinity pentamidine transporter. It was found that phosphonium drugs act slowly to clear a trypanosome population but that only a short exposure time is needed for irreversible damage to the cells. A comparative molecular field analysis model (CoMFA) was generated to gain insights into the SAR of this class of compounds, identifying key features for trypanocidal activity.
我们合成了一系列 73 种膦盐和 10 种单膦盐衍生物，并在体外对几种野生型和耐药型锥虫（T. b. rhodesiense STIB900、T. b. brucei 株 427、TbAT1-KO 和 TbB48）进行了测试。超过一半的测试化合物对这些寄生虫表现出亚微摩尔 EC50。这些化合物与现有的双脒类疗法（如戊烷脒）没有交叉耐药性。在大多数情况下，这些化合物对人细胞系表现出良好的选择性指数。尽管一些双膦化合物抑制低亲和力戊烷脒转运体，但已知的 T. b. brucei 药物转运体对杀锥虫活性不是必需的。研究发现，膦类药物清除锥虫种群的作用缓慢，但对细胞造成不可逆损伤只需要很短的暴露时间。我们生成了一个比较分子场分析模型（CoMFA），以深入了解这类化合物的 SAR，确定杀锥虫活性的关键特征。
