RESUMO
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.
Assuntos
Antiprotozoários/química , Inibidores Enzimáticos/química , N-Glicosil Hidrolases/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Trichomonas vaginalis/enzimologia , Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Ligantes , N-Glicosil Hidrolases/genética , N-Glicosil Hidrolases/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/química , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/genéticaRESUMO
Nucleoside salvage pathway enzymes used by Trichomonas vaginalis are distinct from the pathway involved in activation of existing 5-nitroimidazole drugs. They thus represent excellent targets for developing novel, mechanism-based antitrichomonal agents. The purine-specific adenosine/guanosine preferring ribohydrolase (AGNH) was screened against the NIH Clinical Collection to assess its druggability. Eight compounds, including five flavonoids, were identified with IC50 values ⩽10 µM and confirmed in counter screens run in the presence of detergent. The inhibitors are structurally distinct from inhibitors of the pyrimidine-specific uridine ribohydrolase (UNH) thus indicating that AGNH is a distinct, druggable target from UNH.