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

Andriy Buchynskyy; J Robert Gillespie; Zackary M Herbst; Ranae M Ranade; Frederick S Buckner; Michael H Gelb

doi:10.1021/acsmedchemlett.7b00230

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

ACS Med Chem Lett. 2017 Jul 10;8(8):886-891. doi: 10.1021/acsmedchemlett.7b00230. eCollection 2017 Aug 10.

Authors

Andriy Buchynskyy¹, J Robert Gillespie², Zackary M Herbst², Ranae M Ranade², Frederick S Buckner², Michael H Gelb¹

Affiliations

¹ Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.
² Department of Medicine, University of Washington, Seattle, Washington 98109, United States.

Abstract

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.

Keywords: Human African Trypanosomiasis; Trypanosoma brucei inhibitor; hit-to-lead optimization; thiohydantoins; “sleeping sickness”.

Grants and funding

R01 AI106850/AI/NIAID NIH HHS/United States