| Literature DB >> 31469332 |
Glaécia An Pereira1,2,3, Lucianna H Santos1,4, Steven C Wang5,6, Luan C Martins1, Filipe S Villela1, Weiting Liao5, Marco A Dessoy7, Luiz C Dias7, Adriano D Andricopulo8, Mariana Af Costa9, Ronaldo Ap Nagem9, Conor R Caffrey5, Klaus R Liedl10, Ernesto R Caffarena4, Rafaela S Ferreira1.
Abstract
Aim: 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 Ki = 0.21 μM against rhodesain) and micromolar activity against Trypanosoma brucei brucei. A cheminformatics analysis confirms scaffold novelty, and the inhibitors described have favorable predicted physicochemical properties.Entities:
Keywords: benzimidazole inhibitors; cruzain; parasite cysteine proteases; rhodesain
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Year: 2019 PMID： 31469332 PMCID： PMC6722484 DOI： 10.4155/fmc-2018-0523
Source DB: PubMed Journal: Future Med Chem ISSN： 1756-8919 Impact factor: 3.808