RESUMEN
Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
Asunto(s)
Antituberculosos/síntesis química , Diseño de Fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/química , Pirimidinas/síntesis química , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/sangre , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Femenino , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Nitroimidazoles/sangre , Nitroimidazoles/farmacocinética , Nitroimidazoles/farmacología , Pirimidinas/sangre , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Solubilidad , Relación Estructura-Actividad , Tuberculosis/sangre , Tuberculosis/microbiologíaRESUMEN
A structure-activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.
Asunto(s)
Hepacivirus/enzimología , Piridinas/química , Piridinas/farmacología , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacología , Perros , Hepacivirus/efectos de los fármacos , Humanos , Macaca fascicularis , Ratas , Relación Estructura-ActividadRESUMEN
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Asunto(s)
Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Quinolonas/farmacología , Inhibidores de Topoisomerasa/farmacología , HumanosRESUMEN
A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.
Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Indoles/farmacología , Piridinas/farmacología , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Animales , Antivirales/administración & dosificación , Antivirales/química , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Hepacivirus/genética , Humanos , Indoles/síntesis química , Indoles/química , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/genéticaRESUMEN
A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
Asunto(s)
Acetamidas/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Oxazolidinonas/química , Oxazolidinonas/farmacología , Piridinas/química , Antibacterianos/química , Enterococcus/efectos de los fármacos , Linezolid , Estructura Molecular , Oxazolidinonas/síntesis química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.