RESUMO
Combinatorial libraries of N-acylated 5-(S)-aminomethyloxazolidinone derivatives of S-oxide and S,S-dioxide tetrahydro-4(2H)-thiopyranyl and thiomorpholine phenyloxazolidinone series have been synthesized on a solid phase and evaluated for antimicrobial activity. Several novel potent leads have been identified, including orally active oxazolidinones with enhanced activity against respiratory tract infection pathogens Haemophilus influenzae and Moraxella catarrhalis.
Assuntos
Antibacterianos/farmacocinética , Haemophilus influenzae/efeitos dos fármacos , Moraxella catarrhalis/efeitos dos fármacos , Morfolinas/química , Oxazolidinonas/farmacocinética , Óxidos/química , Compostos de Oxigênio/farmacocinética , Animais , Antibacterianos/administração & dosagem , Disponibilidade Biológica , Técnicas de Química Combinatória , Infecções por Haemophilus/microbiologia , Metabolismo dos Lipídeos , Masculino , Testes de Sensibilidade Microbiana , Infecções por Moraxellaceae/microbiologia , Oxazolidinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of