RESUMO
The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon).
Assuntos
Antivirais/farmacologia , Química Farmacêutica/métodos , Hepacivirus/química , Hepacivirus/genética , Pirrolidinas/antagonistas & inibidores , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Replicon/genética , Proteínas não Estruturais Virais/farmacologia , Antivirais/química , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , RNA Viral/química , Proteínas não Estruturais Virais/química , Replicação Viral/efeitos dos fármacosRESUMO
HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported.
Assuntos
Hepacivirus/enzimologia , Pirrolidinas/química , Pirrolidinas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Técnicas de Química Combinatória , Estrutura MolecularRESUMO
Pantothenate kinase (CoaA) catalyzes the first step of the coenzyme A biosynthetic pathway. Here we report the identification of the Staphylococcus aureus coaA gene and characterization of the enzyme. We have also identified a series of low-molecular-weight compounds which are effective inhibitors of S. aureus CoaA.