RESUMEN
Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection.
Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/antagonistas & inhibidores , Benzodiazepinas/química , Administración Oral , Animales , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Benzodiazepinas/farmacocinética , Benzodiazepinas/uso terapéutico , Células CHO , Clostridioides difficile/metabolismo , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/veterinaria , Cricetinae , Cricetulus , Semivida , Ratones , Relación Estructura-ActividadRESUMEN
The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50â¯=â¯0.77⯵M). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50â¯=â¯1â¯nM) and 13â¯l(IC50â¯=â¯7â¯nM) which were chosen as leads for further optimization.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/antagonistas & inhibidores , Clostridioides difficile/efectos de los fármacos , Nucleotidasas/antagonistas & inhibidores , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacocinética , Apoptosis/efectos de los fármacos , Células CHO , Cricetulus , Estabilidad de Medicamentos , Enterotoxinas/antagonistas & inhibidores , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon-carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.
Asunto(s)
Antibacterianos/síntesis química , Quinolonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Eritromicina/síntesis química , Eritromicina/farmacología , Eritromicina/análogos & derivados , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
A series of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives has been synthesized. Several functional groups were identified as the optimal C3-substituents, and the best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
