Ligand-Efficient Inhibitors of Trichomonas vaginalis Adenosine/Guanosine Preferring Nucleoside Ribohydrolase.
ACS Infect Dis
; 5(3): 345-352, 2019 03 08.
Article
em En
| MEDLINE
| ID: mdl-30701958
ABSTRACT
Trichomoniasis is caused by the parasitic protozoan Trichomonas vaginalis and is the most prevalent, nonviral sexually transmitted disease. The parasite has shown increasing resistance to the current 5-nitroimidazole therapies indicating the need for new therapies with different mechanisms. T. vaginalis is an obligate parasite that scavenges nucleosides from host cells and then uses salvage pathway enzymes to obtain the nucleobases. The adenosine/guanosine preferring nucleoside ribohydrolase was screened against a 2000-compound diversity fragment library using a 1H NMR-based activity assay. Three classes of inhibitors with more than five representatives were identified bis-aryl phenols, amino bicyclic pyrimidines, and aryl acetamides. Among the active fragments were 10 compounds with ligand efficiency values greater than 0.5, including five with IC50 values <10 µM. Jump-dilution and detergent counter screens validated reversible, target-specific activity. The data reveals an emerging SAR that is guiding our medicinal chemistry efforts aimed at discovering compounds with nanomolar potency.
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Base de dados:
MEDLINE
Assunto principal:
Trichomonas vaginalis
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Proteínas de Protozoários
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Inibidores Enzimáticos
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Antiprotozoários
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N-Glicosil Hidrolases
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article