ABSTRACT
Novel oxazolidinone antibacterials bearing a variety of 3-indolylglyoxamide substituents have been explored in an effort to improve the spectrum and potency of this class of agents. A subclass of this series was also made with the diversity at C-5 terminus. These derivatives have been screened against a panel of clinically relevant Gram-positive pathogens and fastidious Gram-negative organisms. Several analogs in this series were identified with in vitro activity superior to linezolid (MIC=0.25-2 microg/mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC=2-4 microg/mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model.
Subject(s)
Acetamides/pharmacology , Anti-Bacterial Agents , Indoles/chemistry , Oxazolidinones/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Disease Models, Animal , Enterococcus faecalis/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Haemophilus influenzae/drug effects , Linezolid , Methicillin Resistance/drug effects , Mice , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Oxazolidinones/pharmacokinetics , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Vancomycin Resistance/drug effectsABSTRACT
The syntheses of a number of novel oxazolidinone analogues possessing an urea functionality are reported. While the urea derivatives possessing aliphatic and aromatic groups were prepared by the more conventional isocyanate method, the derivatives possessing heterocyclic rings were synthesized by a relatively uncommon but otherwise efficient carbamate chemistry. Though the SAR resulted in novel compounds possessing in vitro activity equivalent to Linezolid, the compounds possess a range of substituents that are amenable for altering physicochemical properties of the resultant drug. The antibacterial activity was found to be not sensitive to the functional groups attached to the urea site regardless of the size and electronic characteristics. Based on in vivo results, one molecule has been identified as a candidate and additional work such as salt selection, scale-up, etc., are currently underway to take the molecule further through development.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Enterococcus faecium/drug effects , Microbial Sensitivity Tests , Oxazolidinones/chemical synthesis , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
OBJECTIVES AND METHODS: DRF 8417, a novel oxazolidinone, has been evaluated against Gram-positive and fastidious Gram-negative bacteria. In vitro activity of DRF 8417 was determined by broth microdilution method and in vivo efficacy studies were carried out in different murine systemic infection models. RESULTS: DRF 8417 exhibited potent activity against Gram-positive pathogens with MIC(50) and MIC(90) values ranging from 0.06 to 1 mg/L. MICs against Haemophilus influenzae and Moraxella catarrhalis were one to two dilutions lower than those of linezolid. The in vivo efficacy, by oral route, in different susceptible and resistant Gram-positive systemic bacterial infection models ranged from 2.0 to 2.9 mg/kg. CONCLUSIONS: These studies displayed the excellent in vitro and in vivo activity of DRF 8417 against Gram-positive pathogens and lower MICs when compared with linezolid against H. influenzae and M. catarrhalis.
Subject(s)
Anti-Infective Agents , Gram-Negative Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Cocci/drug effects , Haemophilus influenzae/drug effects , Moraxella catarrhalis/drug effects , Oxazolidinones , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Disease Models, Animal , Female , Gram-Negative Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/microbiology , Haemophilus Infections/drug therapy , Haemophilus Infections/microbiology , Haemophilus influenzae/enzymology , Humans , Male , Mice , Microbial Sensitivity Tests , Moraxellaceae Infections/drug therapy , Moraxellaceae Infections/microbiology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Specific Pathogen-Free Organisms , Treatment Outcome , beta-Lactam Resistance , beta-Lactamases/metabolismABSTRACT
Ether and methanol extracts of Ixora coccinea dry leaves were tested for their antimicrobial activity. Ether fraction was found to be more active than the methanol fraction.
