1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
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DOI：
10.1021/acsmedchemlett.7b00230
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发表时间：
2017-08-01
影响因子：
4.2
通讯作者：
Gelb, Michael H.
中科院分区：
文献类型：
--
作者：
Buchynskyy, Andriy;Gillespie, J. Robert;Gelb, Michael H.
A high throughput screening and subsequent hit validation identified compound 1 as an inhibitor of Ttypanosoma brucei parasite growth. Extensive structure activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzy1)-3-(4-dimethylamino-3-chloropheny1)-2-thiohydantoin (68) and 1-(2-chloro-4-fluorobenzy1)-3-(4-dimethylamino-3-methoxypheny1)-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.
