RESUMEN
RWJ-416457, an investigational pyrrolopyrazolyl-substituted oxazolidinone, inhibited the growth of linezolid-susceptible staphylococci, enterococci, and streptococci at concentrations of < or =4 microg/ml, generally exhibiting two- to fourfold-greater potency than that of linezolid. Time-kill studies demonstrated bacteriostatic effects for both RWJ-416457 and linezolid.
Asunto(s)
Antibacterianos/farmacología , Oxazolidinonas/farmacología , Acetamidas/química , Antibacterianos/química , Farmacorresistencia Bacteriana , Enterococcus/efectos de los fármacos , Linezolid , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/química , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacosRESUMEN
We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Indazoles/farmacología , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/química , Diseño de Fármacos , Resistencia a Múltiples Medicamentos/fisiología , Inhibidores Enzimáticos/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
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
Oxazolidinone antibacterial agents, where the morpholino group of linezolid was replaced with an N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The functionality attached to the piperidine nitrogen was varied extensively to determine the SAR for this series. One of the most potent compounds, 11, showed in vivo efficacy upon subcutaneous administration in a Staphylococcus aureus Smith murine systemic infection.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Oxazolidinonas/química , Oxazolidinonas/farmacología , Animales , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Pruebas de Sensibilidad Microbiana , 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.