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
Combinatorial libraries of N-acylated 5-(S)-aminomethyloxazolidinone derivatives of S-oxide and S,S-dioxide tetrahydro-4(2H)-thiopyranyl and thiomorpholine phenyloxazolidinone series have been synthesized on a solid phase and evaluated for antimicrobial activity. Several novel potent leads have been identified, including orally active oxazolidinones with enhanced activity against respiratory tract infection pathogens Haemophilus influenzae and Moraxella catarrhalis.
Asunto(s)
Antibacterianos/farmacocinética , Haemophilus influenzae/efectos de los fármacos , Moraxella catarrhalis/efectos de los fármacos , Morfolinas/química , Oxazolidinonas/farmacocinética , Óxidos/química , Compuestos de Oxígeno/farmacocinética , Animales , Antibacterianos/administración & dosificación , Disponibilidad Biológica , Técnicas Químicas Combinatorias , Infecciones por Haemophilus/microbiología , Metabolismo de los Lípidos , Masculino , Pruebas de Sensibilidad Microbiana , Infecciones por Moraxellaceae/microbiología , Oxazolidinonas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The oxazolidinone linezolid represents a new antibacterial class of potential benefit in managing multidrug-resistant gram-positive infections, including those caused by Streptococcus pneumoniae. In a gerbil model of acute otitis media (AOM) induced by either penicillin-resistant S. pneumoniae (PRSP; amoxicillin MIC = 8 micro g/ml, linezolid MIC = 1 micro g/ml) or penicillin-susceptible S. pneumoniae (PSSP; amoxicillin MIC = 0.015 micro g/ml, linezolid MIC = 1 micro g/ml), we explored the plasma and ear fluid levels of linezolid required to demonstrate efficacy. Threshold pathogen doses required to induce bilateral AOM (1,500 CFU/ear with PRSP; 30 CFU/ear with PSSP) were administered to gerbils by intrabullar injection on day 0. At peak infection ( approximately 10(6) to 10(7) CFU/ear flush; day 2 for PRSP-AOM and day 3 for PSSP-AOM), twice-a-day oral doses of linezolid, amoxicillin, or vehicle were administered over 4.5 days prior to collection and assay of middle ear effluents for S. pneumoniae content. Linezolid doses of >/=10 mg/kg of body weight induced significant cure rates of >/=72% versus both PRSP and PSSP infections, whereas amoxicillin at MIC of >/=42%, a C(max)/MIC ratio of >/=3.1, and a (24-h area under the curve)/MIC ratio of >/=30 h. Application of this model will be useful in defining preclinical pharmacodynamic relationships of novel antibiotics necessary to cure S. pneumoniae-induced AOM.
Asunto(s)
Acetamidas/farmacocinética , Antibacterianos/farmacocinética , Otitis Media/tratamiento farmacológico , Oxazolidinonas/farmacocinética , Infecciones Neumocócicas/tratamiento farmacológico , Acetamidas/uso terapéutico , Enfermedad Aguda , Administración Oral , Animales , Área Bajo la Curva , Modelos Animales de Enfermedad , Femenino , Gerbillinae , Linezolid , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/uso terapéutico , Resistencia a las Penicilinas , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
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.
