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Type: Artigo
Title: Benzimidazole inhibitors of the major cysteine protease of Trypanosoma brucei
Author: Pereira, Glaecia A. N.
Santos, Lucianna H.
Wang, Steven C.
Martins, Luan C.
Villela, Filipe S.
Liao, Weiting
Dessoy, Marco A.
Dias, Luiz C.
Andricopulo, Adriano D.
Nagem, Ronaldo A. P.
Caffrey, Conor R.
Liedl, Klaus R.
Caffarena, Ernesto R.
Ferreira, Rafaela S.
Abstract: Limitations in available therapies for trypanosomiases indicate the need for improved medicines. Cysteine proteases cruzain and rhodesain are validated targets for treatment of Chagas disease and human African trypanosomiasis. Previous studies reported a benzimidazole series as potent cruzain inhibitors. Results & methodology: Considering the high similarity between these proteases, we evaluated 40 benzimidazoles against rhodesain. We describe their structure-activity relationships (SAR), revealing trends similar to those observed for cruzain and features that lead to enzyme selectivity. This series comprises noncovalent competitive inhibitors (best K-i = 0.21 mu M against rhodesain) and micromolar activity against Trypanosoma brucei brucei. A cheminformatics analysis confirms scaffold novelty, and the inhibitors described have favorable predicted physicochemical properties. Conclusion: Our results support this series as a starting point for new human African trypanosomiasis medicines
Subject: Tripanossomo
Country: Reino Unido
Editor: Future Science
Rights: Fechado
Identifier DOI: 10.4155/fmc-2018-0523
Date Issue: 2019
Appears in Collections:IQ - Artigos e Outros Documentos

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