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
Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.