Novartis Institute for Tropical Diseases, 10 Biopolis Road, no. 05-01 Chromos, Singapore 138670.
J Med Chem. 2010 Jul 22;53(14):5155-64. doi: 10.1021/jm100410f.
The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.
本文描述了一系列螺环四氢 β-咔啉的抗疟原虫活性。从野生型恶性疟原虫的表型筛选中鉴定出外消旋螺氮杂吲哚（1），其体外 IC50 为 90 nM。通过对 1 进行结构活性关系优化，得到化合物 20a（IC50=0.2 nM），包括确定活性 1R，3S 对映异构体和消除代谢缺陷。该系列药物的药代动力学特性得到改善，在感染疟原虫的疟鼠模型中具有优异的口服疗效，其中 30 mg/kg 剂量，每日三次，连续用药 3 天，5 只鼠中有 4 只完全治愈。
