RESUMEN
The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.
Asunto(s)
Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Carbapenémicos/química , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Espectrofotometría , Relación Estructura-ActividadRESUMEN
A new series of carbapenems, having a saturated or partially unsaturated heterocycle at C-2, has been synthesised. The in vitro antibacterial activity of these compounds and their stability to human dehydropeptidase-1 (DHP-1) are described. The stereochemistry of the C-2 side-chain and the presence of a double bond in the heterocycle were shown to have significant effects on the stabilities of the compounds to DHP-1.
Asunto(s)
Bacterias/efectos de los fármacos , Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Carbapenémicos/química , Dipeptidasas/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Estructura MolecularRESUMEN
(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-[(Z)-[(S)-carboxy(3,4- dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(1-methylaminopyri dinium-4-thiomethyl)ceph-3-em-4-carboxylate sodium salt (BRL 57342, 1f) combines excellent in vitro antibacterial potency against Gram-positive and Gram-negative bacteria, including P. aeruginosa and Acinetobacter spp., with excellent stability to extended spectrum beta-lactamases. This potency is reflected in in vivo efficacy studies.
Asunto(s)
Cefalosporinas/síntesis química , Animales , Cefalosporinas/química , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Saimiri , Relación Estructura-ActividadRESUMEN
The synthesis and antibacterial activity of a series of 3-(1-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins is described. All the derivatives showed good potency and stability to bacterial beta-lactamases. The antibacterial efficacy seen with the N-alkyl pyridinium substituents was enhanced by the introduction of a catecholic side chain at C-7 and by preparation of N-(substituted amino)pyridinium derivatives.
Asunto(s)
Bacterias/efectos de los fármacos , Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The synthesis and antibacterial activity of a series of beta-lactamase stable, broad spectrum 7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-cephalo sporins, characterised by a C-3-[N-(substituted-amino)pyridinium-4-thiomethyl] group, is described. Gram-positive and Gram-negative bacteria including extended spectrum beta-lactamase-producing strains were most susceptible to the N-amino- and N-methylamino derivatives (3a) and (3b); with the exception of Pseudomonas aeruginosa, (3b) was more active in vitro and in vivo than cefpirome or ceftazidime.
Asunto(s)
Cefalosporinas/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Animales , Cefalosporinas/farmacología , Cefalosporinas/toxicidad , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The synthesis and antibacterial activity of 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl) carbonylamino] acetamido]-7 alpha-formamidocephalosporins with various substituents at the C-3 position of the cephalosporin nucleus is described. Inhibition of Gram-positive and Gram-negative bacteria including beta-lactamase producing strains was observed with phenyl as the aryl residue. The 3,4-dihydroxyphenyl group further enhanced the activity against Gram-negative organisms; in this series, the 3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] and 3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl] analogues (2 and 12b) exhibited exceptional activity against Gram-negative bacteria, including Pseudomonas aeruginosa.