1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy

被引：36

作者：

Buchynskyy, Andriy ^{[1
]}

Gillespie, J. Robert ^{[2
]}

Herbst, Zackary M. ^{[2
]}

Ranade, Ranae M. ^{[2
]}

Buckner, Frederick S. ^{[2
]}

Gelb, Michael H. ^{[1
]}

机构：

[1] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[2] Univ Washington, Dept Med, Seattle, WA 98109 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 08期

基金：

美国国家卫生研究院;

关键词：

Human African Trypanosomiasis; sleeping sickness; Trypanosoma brucei inhibitor; thiohydantoins; hit-to-lead optimization; HYDANTOINS; 2-THIOHYDANTOINS; INHIBITORS; ANALOGS; DESIGN;

D O I：

10.1021/acsmedchemlett.7b00230

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：886 / 891

页数：6

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