RESUMEN
Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Fenoles/química , Tiadiazoles/química , Acetamidas/síntesis química , Acetamidas/química , Acetamidas/farmacología , Animales , Antibacterianos/química , Linezolid , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/química , Ratas , Relación Estructura-Actividad , Tioacetamida/síntesis química , Tioacetamida/química , Tioacetamida/farmacologíaRESUMEN
Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms. The effect of ring nitrogen position and N-substitution on antibacterial activity is examined.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Benzazepinas/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Acetamidas/farmacología , Animales , Antibacterianos/química , Bacterias Gramnegativas/efectos de los fármacos , Linezolid , Ratones , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/química , Relación Estructura-ActividadRESUMEN
A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.