RESUMEN
We describe the synthesis and antibacterial activity of a series of tetracyclic naphthyridones. The members of this series act primarily via inhibition of bacterial translation and belong to the class of novel ribosome inhibitors (NRIs). In this paper we explore the structure-activity relationships (SAR) of these compounds to measure their ability both to inhibit bacterial translation and also to inhibit the growth of bacterial cells in culture. The most active of these compounds inhibit Streptococcus pneumoniae translation at concentrations of <5 microM and have minimum inhibitory concentrations (MICs) of <8 microg/mL against clinically relevant strains of bacteria.
Asunto(s)
Antibacterianos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Naftiridinas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Linfocitos B/efectos de los fármacos , Farmacorresistencia Bacteriana , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Naftiridinas/química , Naftiridinas/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Estereoisomerismo , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.