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

[Image: see text] 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-...

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Autores principales: Buchynskyy, Andriy, Gillespie, J. Robert, Herbst, Zackary M., Ranade, Ranae M., Buckner, Frederick S., Gelb, Michael H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2017
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554913/
https://www.ncbi.nlm.nih.gov/pubmed/28835807
http://dx.doi.org/10.1021/acsmedchemlett.7b00230
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author Buchynskyy, Andriy
Gillespie, J. Robert
Herbst, Zackary M.
Ranade, Ranae M.
Buckner, Frederick S.
Gelb, Michael H.
author_facet Buchynskyy, Andriy
Gillespie, J. Robert
Herbst, Zackary M.
Ranade, Ranae M.
Buckner, Frederick S.
Gelb, Michael H.
author_sort Buchynskyy, Andriy
collection PubMed
description [Image: see text] 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 EC(50) 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.
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spelling pubmed-55549132017-08-23 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy Buchynskyy, Andriy Gillespie, J. Robert Herbst, Zackary M. Ranade, Ranae M. Buckner, Frederick S. Gelb, Michael H. ACS Med Chem Lett [Image: see text] 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 EC(50) 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. American Chemical Society 2017-07-10 /pmc/articles/PMC5554913/ /pubmed/28835807 http://dx.doi.org/10.1021/acsmedchemlett.7b00230 Text en Copyright © 2017 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Buchynskyy, Andriy
Gillespie, J. Robert
Herbst, Zackary M.
Ranade, Ranae M.
Buckner, Frederick S.
Gelb, Michael H.
1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
title 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
title_full 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
title_fullStr 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
title_full_unstemmed 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
title_short 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy
title_sort 1-benzyl-3-aryl-2-thiohydantoin derivatives as new anti-trypanosoma brucei agents: sar and in vivo efficacy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554913/
https://www.ncbi.nlm.nih.gov/pubmed/28835807
http://dx.doi.org/10.1021/acsmedchemlett.7b00230
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