RESUMEN
The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC90 value of 8⯵g/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8â¯mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections.
Asunto(s)
Antibacterianos/metabolismo , Compuestos de Azabiciclo/química , ADN/metabolismo , Niacina/análogos & derivados , Piridinas/química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/metabolismo , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , ADN/química , Evaluación Preclínica de Medicamentos , Escherichia coli/efectos de los fármacos , Escherichia coli/patogenicidad , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/veterinaria , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Niacina/metabolismo , Niacina/farmacología , Niacina/uso terapéutico , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
The hepatitis C virus NS3 protein contains an N-terminal serine protease and a C-terminal helicase that unwinds RNA or DNA duplexes. The HCV NS3 protein is the target for several antiviral drugs in clinical trials, which inhibit the protease function. A method is reported to simultaneously monitor the helicase and protease function of the NS3 protein in a single reaction using fluorescence spectroscopy and a single chain recombinant protein where NS3 is fused to its protease activator NS4A. The method monitors both activities together in real time and is amenable to high-throughput screening. This new procedure could be used to identify compounds that inhibit both the helicase and protease activity of NS3.