ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Haemophilus influenzae/drug effects , Moraxella catarrhalis/drug effects , Morpholines/chemistry , Oxazolidinones/pharmacokinetics , Oxides/chemistry , Oxygen Compounds/pharmacokinetics , Animals , Anti-Bacterial Agents/administration & dosage , Biological Availability , Combinatorial Chemistry Techniques , Haemophilus Infections/microbiology , Lipid Metabolism , Male , Microbial Sensitivity Tests , Moraxellaceae Infections/microbiology , Oxazolidinones/administration & dosage , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Antimicrobial compounds incorporating oxazolidinone and quinolone pharmacophore substructures have been synthesized and evaluated. Representative analogues 2, 5, and 6 display an improved potency versus linezolid against gram-positive and fastidious gram-negative pathogens. The compounds are also active against linezolid- and ciprofloxacin-resistant Staphylococcus aureus and Enterococcus faecium strains. The MOA for these new antimicrobials is consistent with a combination of protein synthesis and gyrase A/topoisomerase IV inhibition, with a structure-dependent degree of the contribution from each inhibitory mechanism.
