Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1&2, Université Montpellier 2 , cc 1705, place E. Bataillon, 34095 Montpellier, France.
J Med Chem. 2012 May 24;55(10):4619-28. doi: 10.1021/jm3000328. Epub 2012 May 16.
We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.
我们在此报告了一系列 15 个二硫代酯前药的设计、合成和生物筛选，这些前药是 Albiziaziolium 溴化物（T3/SAR97276，化合物 1）的前体，Albiziaziolium 溴化物是一种胆碱类似物，目前正在临床试验（二期）中评估用于治疗严重疟疾。预计这些前药将通过二硫键的酶还原反应转化回活性双噻唑鎓盐。为了提高这些前药的水溶性，在噻唑鎓侧链上引入了一个氨基酸残基（缬氨酸或赖氨酸）或磷酸基。大多数新型衍生物对恶性疟原虫表现出很强的体外抗疟活性。口服给药后，与母体药物相比，环状二硫代酯前药 8 显示出了最佳的口服疗效改善。
