RESUMEN
A novel series of oxazolidinones were synthesized in which the morpholine C-ring of linezolid was replaced with homomorpholine. In addition to investigating the effect of a homomorpholine C-ring on antibacterial activity, the effect of des-, mono-, di-, and tri-fluoro substitution on the phenyl B-ring was investigated as well. Various C-5 functional groups were also examined, including acetamides and triazoles and carboxamides.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Morfolinas/química , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Antibacterianos/química , Oxazolidinonas/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: Higenamine is a stimulant with cardiovascular properties recently prohibited in sport by the World Anti-Doping Agency (WADA). Higenamine is also a natural constituent of several traditional botanical remedies and is listed as an ingredient in weight loss and sports supplements sold over-the-counter in the United States. OBJECTIVES: We analyzed dietary supplements available for sale in the United States prior to WADA's prohibition of higenamine in sport for the presence and quantity of higenamine. METHODS: All supplements labeled as containing higenamine or a synonym (i.e., norcoclaurine or demethylcoclaurine) available for sale in the United States were identified. For each brand, one sample was analyzed by NSF International (Ann Arbor, MI) and one sample by the Netherland's National Institute for Public Health and the Environment (RIVM). NSF International carried out qualitative and quantitative analyses using ultra high performance liquid chromatography (UHPLC) with tandem mass spectrometry. RIVM carried out qualitative analysis using UHPLC quadrupole time of flight mass spectrometry for an independent confirmation of identity. RESULTS: Twenty-four products were analyzed. The majority of supplements were marketed as either weight loss (11/24; 46%) or sports/energy supplements (11/24; 46%); two brands did not list a labeled indication. The quantity of higenamine (±95% CI) ranged from trace amounts to 62 ± 6.0 mg per serving. Consumers could be exposed to up to 110 ± 11 mg of higenamine per day when following recommended serving sizes provided on the label. Five products (5/24; 21%) listed an amount of higenamine, but none were accurately labeled; the quantity in these supplements ranged from <0.01% to 200% of the quantity listed on the label. CONCLUSION: Dosages of up to 62 ± 6.0 mg per serving of the stimulant higenamine were found in dietary supplements sold in the United States.
Asunto(s)
Alcaloides/análisis , Fármacos Antiobesidad/análisis , Suplementos Dietéticos/análisis , Doping en los Deportes , Tetrahidroisoquinolinas/análisis , Cromatografía Líquida de Alta Presión , Humanos , Espectrometría de MasasRESUMEN
Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.
Asunto(s)
Antibacterianos/síntesis química , Óxidos S-Cíclicos/síntesis química , Oxazolidinonas/síntesis química , Acetamidas/farmacología , Administración Oral , Animales , Antibacterianos/farmacología , Antibacterianos/toxicidad , Disponibilidad Biológica , Óxidos S-Cíclicos/farmacología , Óxidos S-Cíclicos/toxicidad , Perros , Farmacorresistencia Bacteriana , Femenino , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Inyecciones Intravenosas , Linezolid , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/toxicidad , Oxazolidinonas/farmacología , Oxazolidinonas/toxicidad , Ratas , Ratas Sprague-Dawley , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus pyogenes , Relación Estructura-ActividadRESUMEN
A novel series of conformationally restricted oxazolidinones was synthesized, in which the heterocyclic D ring was substituted with various amino groups. Several analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms. Certain amino-substituted analogs also exhibited improved aqueous solubility compared to the corresponding un-substituted heterocyclic D-ring analogs.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Oxazolidinonas/química , Oxazolidinonas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacología , Pirazoles/farmacología , Estructura Molecular , Pirazoles/química , Relación Estructura-ActividadRESUMEN
We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.