Evaluation of dipeptide nitriles as inhibitors of rhodesain, a major cysteine protease of Trypanosoma brucei.
Bioorg Med Chem Lett
; 27(1): 45-50, 2017 01 01.
Article
em En
| MEDLINE
| ID: mdl-27890381
ABSTRACT
A series of dipeptide nitriles known as inhibitors of mammalian cathepsins were evaluated for inhibition of rhodesain, the cathepsin L-like protease of Trypanosoma brucei. Compound 35 consisting of a Leu residue fitting into the S2 pocket and a triarylic moiety consisting of thiophene, a 1,2,4-oxadiazole and a phenyl ring fitting into the S3 pocket, and compound 33 with a 3-bromo-Phe residue (S2) and a biphenyl fragment (S3) were found to inhibit rhodesain in the single-digit nanomolar range. The observed steep structure-activity relationship could be explained by covalent docking simulations. With their high selectivity indices (ca. 200) and the good antitrypanosomal activity (8µM) the compounds represent promising starting points for new rhodesain inhibitors.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trypanosoma brucei brucei
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Cisteína Endopeptidases
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Inibidores de Cisteína Proteinase
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Dipeptídeos
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Nitrilas
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Antituberculosos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article