RESUMEN
QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (-)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the beta subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores de Topoisomerasa II , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Área Bajo la Curva , Bacterias/enzimología , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/prevención & control , Línea Celular , Proliferación Celular/efectos de los fármacos , Tasa de Depuración Metabólica , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , EstereoisomerismoRESUMEN
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
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 oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.
Asunto(s)
Antibacterianos , Diseño de Fármacos , Hidroquinonas , Indoles , Oxazinas , Oxazolidinonas , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Hidroquinonas/síntesis química , Hidroquinonas/farmacocinética , Hidroquinonas/farmacología , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Pruebas de Sensibilidad Microbiana , Oxazinas/síntesis química , Oxazinas/farmacocinética , Oxazinas/farmacología , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacocinética , Oxazolidinonas/farmacología , Relación Estructura-ActividadRESUMEN
The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings. A number of solutions to the problem of bacterial resistance are possible. The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes. Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity. Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise. Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs. This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacología , Acetamidas/uso terapéutico , Animales , Antibacterianos/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Linezolid , Estructura Molecular , Oxazolidinonas/uso terapéutico , 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.
Asunto(s)
Antibacterianos/síntesis química , Derivados del Benceno/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Isoxazoles/síntesis química , Piperazinas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Derivados del Benceno/química , Derivados del Benceno/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/química , Farmacorresistencia Bacteriana , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Isoxazoles/química , Isoxazoles/farmacología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Piperazinas/química , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Infecciones Estafilocócicas/mortalidad , Staphylococcus aureus , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Linezolid is a new oxazolidinone with potent antibacterial activity against Gram-positive cocci; it uniquely inhibits bacterial translation through inhibition of 70S initiation complex formation. The effects of sub-growth-inhibitory concentrations of linezolid on the expression of various structural and soluble virulence factors of Staphylococcus aureus and Streptococcus pyogenes were examined. For S. aureus, strains Wood 46 and Cowan 1 (NCTC 8532) were used to measure protein A, coagulase, alpha-haemolysin (hla) and delta-haemolysin (hld). For S. pyogenes, strain NCTC 9994 was used to measure M protein, streptolysin O (SLO) and DNase. Coagulase was assayed by clotting of citrated rabbit plasma, and hla, hld and SLO by lysis of rabbit, human and horse erythrocytes, respectively. Protein A and M protein were measured indirectly using bacterial susceptibility to phagocytic ingestion of radiolabelled bacteria by human neutrophils. When S. aureus was grown in 1/2, 1/4 and 1/8 MIC, linezolid, coagulase, hla and hld production were impaired. Susceptibility to phagocytosis was changed by growth in the presence of 1/2 MIC linezolid compared with that in its absence (50.8 +/- 4.1% versus 38.9 +/- 2.9%; P Asunto(s)
Acetamidas/administración & dosificación
, Cocos Grampositivos/efectos de los fármacos
, Oxazolidinonas/administración & dosificación
, Factores de Virulencia/biosíntesis
, Cocos Grampositivos/metabolismo
, Humanos
, Linezolid
, Fagocitos/efectos de los fármacos
, Fagocitos/metabolismo
, Fagocitos/microbiología
, Staphylococcus aureus/efectos de los fármacos
, Staphylococcus aureus/metabolismo
, Streptococcus pyogenes/efectos de los fármacos
, Streptococcus pyogenes/metabolismo