Buchynskyy Andriy, Gillespie J Robert, Herbst Zackary M, Ranade Ranae M, Buckner Frederick S, Gelb Michael H
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.
Department of Medicine, University of Washington, Seattle, Washington 98109, United States.
ACS Med Chem Lett. 2017 Jul 10;8(8):886-891. doi: 10.1021/acsmedchemlett.7b00230. eCollection 2017 Aug 10.
A high throughput screening and subsequent hit validation identified compound as an inhibitor of parasite growth. Extensive structure-activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzyl)-3-(4-dimethylamino-3-chlorophenyl)-2-thiohydantoin () and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3-methoxyphenyl)-2-thiohydantoin (), with a EC of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound . In vivo efficacy experiments of and in an acute mouse model of Human African Trypanosomiasis showed a 100% cure rate after 4 days of oral treatment at 50 mg/kg twice per day.
一次高通量筛选及随后的活性验证确定化合物为寄生虫生长的抑制剂。基于抗寄生虫活性进行的广泛构效关系优化产生了高效能化合物，即1-(4-氟苄基)-3-(4-二甲基氨基-3-氯苯基)-2-硫代乙内酰脲（）和1-(2-氯-4-氟苄基)-3-(4-二甲基氨基-3-甲氧基苯基)-2-硫代乙内酰脲（），其半数有效浓度（EC）分别为3 nM和2 nM。与化合物相比，这代表效能提高了100倍以上。在人类非洲锥虫病急性小鼠模型中对和进行的体内疗效实验显示，每天两次口服50 mg/kg，治疗4天后治愈率为100%。
