1-Benzyl-3-Aryl-2-Thiohydantoin Derivatives As New Anti-Trypanosoma Brucei Agents: Sar And In Vivo Efficacy

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.