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1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2017-07-30 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00230
Andriy Buchynskyy 1 , J. Robert Gillespie 2 , Zackary M. Herbst 2 , Ranae M. Ranade 2 , Frederick S. Buckner 2 , Michael H. Gelb 1
Affiliation  

A high throughput screening and subsequent hit validation identified compound 1 as an inhibitor of Trypanosoma brucei 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 (68) and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3-methoxyphenyl)-2-thiohydantoin (76), with a T. brucei EC50 of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound 1. In vivo efficacy experiments of 68 and 76 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.

中文翻译:

1-苄基-3-芳基-2-硫代乙内酰脲衍生物作为新型抗布鲁氏锥虫剂:SAR和体内功效

高通量筛选和随后的命中验证确定化合物1布鲁氏锥虫寄生虫生长的抑制剂。基于抗寄生虫活性的广泛的结构-活性关系优化导致了高效化合物1-(4-氟苄基)-3-(4-二甲基氨基-3-氯苯基)-2-硫代乙内酰脲(68)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(76),布氏锥虫EC 50分别为3和2 nM。与化合物1相比,这表示效力提高了100倍以上。6876的体内功效实验 在人类非洲锥虫病的急性小鼠模型中,口服治疗每天4次,每天两次,剂量为50 mg / kg,治愈率为100%。
更新日期:2017-07-30
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