RESUMEN
A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
Asunto(s)
Amidas/farmacología , Azetidinas/química , Descubrimiento de Drogas , Enoil-ACP Reductasa (NADH)/metabolismo , Inhibidores Enzimáticos/farmacología , Staphylococcus aureus/enzimología , Amidas/química , Amidas/metabolismo , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Staphylococcus aureus/citología , Relación Estructura-ActividadRESUMEN
Novel oxazolidinone antibacterials bearing a variety of 3-indolylglyoxamide substituents have been explored in an effort to improve the spectrum and potency of this class of agents. A subclass of this series was also made with the diversity at C-5 terminus. These derivatives have been screened against a panel of clinically relevant Gram-positive pathogens and fastidious Gram-negative organisms. Several analogs in this series were identified with in vitro activity superior to linezolid (MIC=0.25-2 microg/mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC=2-4 microg/mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model.
Asunto(s)
Acetamidas/farmacología , Antibacterianos , Indoles/química , Oxazolidinonas/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Modelos Animales de Enfermedad , Enterococcus faecalis/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Haemophilus influenzae/efectos de los fármacos , Linezolid , Resistencia a la Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Oxazolidinonas/farmacocinética , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Resistencia a la Vancomicina/efectos de los fármacosRESUMEN
Novel oxazolidinone antibacterials containing N-hydroxyacetamidine moiety are synthesized with the diversity at C-5 terminus. These compounds have been evaluated against a panel of clinically relevant gram-positive and gram-negative pathogens. Most of the analogs in this series displayed activity superior to Linezolid and in vivo efficacies of selected oxazolidinones are also disclosed herein.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Ácidos Hidroxámicos/química , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Animales , Antibacterianos/química , Modelos Animales de Enfermedad , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Bacterias Grampositivas/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Ratones , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Oxazolidinonas/química , EstereoisomerismoRESUMEN
The effects of natural and synthetic eicosanoids on the diameter of rat interlobular arteries studied in vitro were compared to that of the potent, endogenous vasoconstrictor 20-HETE. Vasoconstrictor activity was optimum for chain lengths of 20-22 carbons with at least one olefin or epoxide between located between C(13)-C(15) and an oxygen substituent at C(20)-C(22). The presence of delta (Zou et al. Am. J. Physiol. 1996, 270, R228; Gebremedhin, D. et al. Am. J. Physiol. 1998, 507, 771)-, delta (Carroll et al. Am. J. Physiol. 1996, 271, R863; Vazquez et al. Life Sci. 1995, 56, 1455)-, or delta (Imig et al. Hypertension 2000, 35, 307; Lopez et al. Amer. J. Physiol. 2001, 281, F420)-olefins had no influence on the vasoconstrictor response whereas the introduction of a C(7)-thiomethylene enhanced potency. A sulfonamide or alcohol, but not a lactone, could replace the C(1)-carboxylate. These data were used to construct a putative binding domain map of the 20-HETE receptor consisting of: (i) a comparatively open, hydrophilic binding site accommodating the C(1)-functionality; (ii) a hydrophobic trough spanning the olefins; (iii) a shallow pocket containing a critical pi-pi binding site in the vicinity of the pi (Ito et al. Am. J. Physiol. 1998, 274, F395; Quigley, R.; Baum, M.; Reddy, K. M.; Griener, J. C.; Falck, J. R. Am. J. Physiol. 2000, 278, F949)-olefin; and (iv) an oxyphilic binding site proximate to the omega-terminus.