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

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.

SUBMITTER: Buchynskyy A

PROVIDER: S-EPMC5554913 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Buchynskyy Andriy A Gillespie J Robert JR Herbst Zackary M ZM Ranade Ranae M RM Buckner Frederick S FS Gelb Michael H MH

ACS medicinal chemistry letters 20170710 8

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 ...[more]

PMID: 28835807

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