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
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