RESUMEN
In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs Asunto(s)
Antibacterianos/química
, Antibacterianos/farmacología
, Farmacorresistencia Bacteriana
, Carbono/química
, Diseño de Fármacos
, Evaluación Preclínica de Medicamentos
, Resistencia a Múltiples Medicamentos
, Bacterias Gramnegativas/efectos de los fármacos
, Bacterias Grampositivas/efectos de los fármacos
, Haemophilus influenzae/efectos de los fármacos
, Pruebas de Sensibilidad Microbiana
, Moraxella catarrhalis/efectos de los fármacos
, Oxazoles
, Pirazoles
, Relación Estructura-Actividad
RESUMEN
A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs
Asunto(s)
Antibacterianos/síntesis química , Azoles/síntesis química , Haemophilus influenzae/efectos de los fármacos , Moraxella catarrhalis/efectos de los fármacos , Oxazoles/síntesis química , Administración Oral , Animales , Antibacterianos/química , Antibacterianos/farmacología , Azoles/química , Azoles/farmacología , Humanos , Resistencia a la Meticilina , Ratones , Pruebas de Sensibilidad Microbiana , Oxazoles/química , Oxazoles/farmacología , Relación Estructura-ActividadAsunto(s)
Antibacterianos/síntesis química , Haemophilus influenzae/efectos de los fármacos , Moraxella catarrhalis/efectos de los fármacos , Oxazoles/síntesis química , Pirazoles/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Recuento de Colonia Microbiana , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Oxazoles/química , Oxazoles/farmacocinética , Oxazoles/farmacología , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirroles/química , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Infecciones Estafilocócicas/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values
Asunto(s)
Antibacterianos/síntesis química , Oxazoles/síntesis química , Oxazolidinonas , Piperazinas/síntesis química , Acetamidas/farmacología , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Células CACO-2 , Enterococcus faecalis/efectos de los fármacos , Humanos , Linezolid , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Oxazoles/química , Oxazoles/metabolismo , Oxazoles/farmacología , Permeabilidad , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-Actividad , Triazenos/síntesis química , Triazenos/química , Triazenos/metabolismo , Triazenos/farmacologíaRESUMEN
A series of conformationally restricted, [6,5,5] and [6,6,5] tricyclic fused oxazolidinones were synthesized and tested for antibacterial activity. Several compounds in the trans-[6,5,5] series demonstrated potent in vitro and in vivo activity. This work provides valuable information regarding the preferred conformational orientation of the oxazolidinones at the binding site.