RESUMO
The methyl and isopropyl esters of (RS)-3-benzothienylglycine were resolved with (+)- and (-)-tartaric acid in acetonitrile to give the corresponding R and S salts. The R-salt 4 was hydrolyzed to (R)-3-benzothienylglycine (5). The amino group in 5 was protected with the Boc function and the protected R amino acid 6 coupled with the p-NB ester of 7-ADCA to give the diprotected cephalosporin 7. After removal of the Boc and p-NB groups, the R isomer of 7-(3-benzothienylglycylamido)deacetoxycephalosporanic acid (1) was obtained. The p-NB ester of epimeric cephalosporin 7 was separated by preparative chromatography into R and S isomers. After removal of the protective groups, the S epimer was isolated. The comparison of antibacterial activity of the R and S epimers and the RS mixture of cephalosporin 1 is reported.
Assuntos
Cefalosporinas/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Administração Oral , Cefalosporinas/isolamento & purificação , Cefalosporinas/farmacologia , Fenômenos Químicos , Química , Glicina/análogos & derivados , Haemophilus influenzae/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos , Estereoisomerismo , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , TiofenosRESUMO
Three positional analogues (4-, 5-, and 7-) of benzothienylglycine and (N-acetylindolinyl)-5-glycine were prepared and coupled to 7-aminodeacetoxycephalosporanic acid (7-ADCA) to give the cephalosporins 17a-c. In addition two isomeric (2,3-b and 3,2-b) thienothiopheneglycines were synthesized and coupled to 7-ADCA to yield cephalosporins 30d and 30e. In vitro testing of these new cephalosporins indicates good activity against Gram-positive bacteria. Against Streptococcus pneumoniae infections compound 25 displayed better mouse protection (both orally and subcutaneously) than cephalexin.
Assuntos
Cefalosporinas/farmacologia , Glicina/análogos & derivados , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Tiofenos/farmacologia , Administração Oral , Animais , Cefalexina/farmacologia , Cefalexina/uso terapêutico , Cefalosporinas/síntese química , Fenômenos Químicos , Química , Glicina/síntese química , Glicina/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Indóis/síntese química , Indóis/uso terapêutico , Camundongos , Infecções Pneumocócicas/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
A structure-activity relationship study of a number of orally absorbed cephalosporins together with their syntheses is described. These new cephalosporins are benzothienyl- and naphthylglycine derivatives of 7-aminodeacetoxycephalosporanic acid. Several different synthetic methods for the glycine side chains, their protection, and the final acylations are reported. Several of these analogues were more active than cephalexin both in vitro and in vivo against commonly encountered Gram-positive bacteria. (R)-7-(3-Benzothienylglycylamido)-3-methyl-3-cephem-4-carboxylic acid (1R) has emerged as a potent antibacterial agent and is currently undergoing preclinical evaluation.