Novel and potent oxazolidinone antibacterials featuring 3-indolylglyoxamide substituents

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 18; pp. 5150 - 5155
• Main Authors: Takhi, Mohamed, Singh, Gurpreet, Murugan, C., Thaplyyal, Nirvesh, Maitra, Soma, Bhaskarreddy, K.M., Amarnath, P.V.S., Mallik, Arundhuti, Harisudan, T., Trivedi, Ravi Kumar, Sreenivas, K., Selvakumar, N., Iqbal, Javed
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.09.2008; Elsevier
• Subjects: Acetamides - pharmacology; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibacterials; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Disease Models, Animal; Enterococcus faecalis - drug effects; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Haemophilus influenzae - drug effects; Indole; Indoles - chemistry; Linezolid; Medical sciences; Methicillin Resistance - drug effects; Mice; Microbial Sensitivity Tests; Molecular Structure; Oxazolidinones; Oxazolidinones - chemical synthesis; Oxazolidinones - chemistry; Oxazolidinones - pharmacokinetics; Oxazolidinones - pharmacology; Pharmacology. Drug treatments; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Vancomycin Resistance - drug effects; Linezolid; Antibacterials; Oxazolidinones; Indole; Enterococcus faecalis; Ketoamide; Nitrogen heterocycle; Organic carbamate; Haemophilus influenzae; Structure activity relation; Thioamide; Bicyclic compound; Bacteria; Micrococcales; Micrococcaceae; Aromatic compound; Chemical synthesis; Oxazole derivatives; Staphylococcus aureus; Halogen Organic compounds; Oxygen nitrogen heterocycle; Rodentia; Benzene derivatives; Oral administration; Organic thiocarbamate; In vitro; Infection; Pasteurellaceae; Streptococcaceae; Enterococcus faecium; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Oxazolidinone derivative; Bacteriosis; Carboxamide; Moraxella catarrhalis; Piperazine derivatives; Antibacterial agent; Pharmacokinetics
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.03.043

The synthesis and antibacterial activity of novel oxazolidinones possessing indolylglyoxamide moiety on piperazine scaffold have been disclosed. 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 μg/mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC = 2–4 μg/mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model.