RESUMEN
A new class of 1 beta-methylcarbapenems bearing a doubly quaternarized 1,4-diazabicyclooctane (DABCO) substituted dithiocarbamate moiety at the C-2 side chain was prepared, and the biological profiles of the compounds, including in vitro and in vivo anti-MRSA activity and DHP-I susceptibility, were evaluated to identify a carbapenem derivative that was superior to BO-3482 (1). As a result, we discovered a 1 beta-methyl-2-[4-(4-carbamoylmethyl-1,4-diazabicyclo[2,2,2]octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio]carbapenem, 14a showing greater than 2-fold better anti-MRSA activity in a mouse infection model and 3-fold better DHP-I susceptibility as compared with BO-3482 (1).
Asunto(s)
Compuestos Aza/química , Compuestos Aza/farmacología , Carbapenémicos/química , Carbapenémicos/farmacología , Resistencia a la Meticilina , Piridinas/química , Piridinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Compuestos Aza/metabolismo , Proteínas Sanguíneas/metabolismo , Carbapenémicos/metabolismo , Dipeptidasas/metabolismo , Evaluación Preclínica de Medicamentos , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Piridinas/metabolismo , Ratas , Ratas Sprague-Dawley , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/fisiología , Relación Estructura-ActividadRESUMEN
1Beta-methylcarbapenems having various 3,5-disubstituted pyrrolidinylthio-side chains at C-2 were designed and synthesized. Evaluation of their antibacterial activities indicated that J-111,347 (1a) is the first example of an extremely broad spectrum antibiotic showing activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as Pseudomonas aeruginosa.
Asunto(s)
Antibacterianos/síntesis química , Carbapenémicos/síntesis química , Pirrolidinas/síntesis química , Antibacterianos/farmacología , Carbapenémicos/farmacología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Pirrolidinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A new series of 1beta-methyl carbapenems, in which a disubstituted-aminothiocarbonylthio moiety was attached to the C-2 position of the carbapenem nucleus, were prepared and evaluated for anti-MRSA activity. These derivatives showed good in vitro antibacterial activity against high-level MRSA, and the finding of good affinity for PBP-2' supported these results. Some of the compounds having favorable protein-binding affinity showed excellent in vivo anti-MRSA activity.
