RESUMO
Novel clarithromycin derivatives with C-4â³ elongated arylalkyl groups were designed, synthesized and evaluated to probe the effect of different lengths of their C-4â³ side chains on the activity against resistant bacterial strains. These derivatives had excellent activity against erythromycin-susceptible Streptococcus pneumoniae, Streptococcus aureus or Streptococcus pyogenes and some of them exhibited greatly improved activity against erythromycin-resistant strains. Compounds 18 and 16, which had the C-4â³ elongated arylalkyl groups with eight atoms from the 4â³-oxygen atom to the terminal benzene ring, were the most effective against S. pneumoniae expressing the erm gene and the erm and mef genes. In contrast, the most potent compounds 3, 5, 9, 17 and 18 against S. pneumoniae expressing the mef gene had C-4â³ elongated arylalkyl groups with three to eight atoms between the 4â³-oxygen atom and the terminal aromatic ring.
Assuntos
Antibacterianos/farmacologia , Claritromicina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Claritromicina/síntese química , Claritromicina/química , Desenho de Fármacos , Farmacorresistência Bacteriana , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
4''-Carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin were designed, synthesized and evaluated. The 4''-carbamate analogs retained excellent activity against erythromycin-susceptible Staphylococcus pneumoniae and showed improved activity against erythromycin-resistant Staphylococcus pneumoniae. Compared with 4''-carbamate analogs, 11,12-cyclic carbonate-4''-carbamate analogs exhibited improved activity against erythromycin-resistant Staphylococcus pneumoniae encoded by the mef gene or the erm and mef genes, and 11,4''-di-O-arylalkylcarbamoyl analogs showed greatly improved activity (0.25-0.5 microg/mL) against erythromycin-resistant Staphylococcus pneumoniae encoded by the erm gene. Among them, the novel series of 11,4''-di-O-arylalkylcarbamoyl analogs 7a-k exhibited potent and balanced activity against susceptible and resistant bacteria. In particular, compounds 7f and 7k were the most effective against susceptible bacteria and resistant bacteria encoded by the erm gene or the mef gene.
