ABSTRACT
Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Phenols/chemistry , Thiadiazoles/chemistry , Acetamides/chemical synthesis , Acetamides/chemistry , Acetamides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Linezolid , Microbial Sensitivity Tests , Oxazolidinones/chemistry , Rats , Structure-Activity Relationship , Thioacetamide/chemical synthesis , Thioacetamide/chemistry , Thioacetamide/pharmacologyABSTRACT
Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms. The effect of ring nitrogen position and N-substitution on antibacterial activity is examined.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Benzazepines/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Acetamides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Gram-Negative Bacteria/drug effects , Linezolid , Mice , Microbial Sensitivity Tests , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzene Derivatives/chemical synthesis , Gram-Positive Bacteria/drug effects , Isoxazoles/chemical synthesis , Piperazines/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Biological Availability , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/chemistry , Drug Resistance, Bacterial , Hepatocytes/metabolism , Humans , In Vitro Techniques , Isoxazoles/chemistry , Isoxazoles/pharmacology , Male , Mice , Microbial Sensitivity Tests , Piperazines/chemistry , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Staphylococcal Infections/mortality , Staphylococcus aureus , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Linezolid is a novel oxazolidinone antibacterial agent active against staphylococci (including methicillin-resistant strains), enterococci (including vancomycin-resistant strains), streptococci (including penicillin-intermediate and -resistant Streptococcus pneumoniae), and other aerobic and facultative bacteria. The agent has also demonstrated activity against a broad spectrum of Gram-positive and Gram-negative anaerobic bacteria. Previous time-kill assessments have shown linezolid to be generally bacteriostatic against staphylococci and enterococci, and bactericidal against streptococci. In this study, an anaerobic glovebox technique was employed to conduct time-kill assessments for four strains of anaerobic Gram-positive, and seven strains of anaerobic Gram-negative bacteria. The time-kill experiment was performed using Anaerobe Broth medium. The drugs were tested at four-fold the minimum inhibitory concentration (MIC), or at the higher concentration of 8mg/L for linezolid, 2mg/L for clindamycin, and 8mg/L for metronidazole. Samples for viable count were taken at 0, 6, and 24h, and plated using the Bioscience International Autospiral DW. Exposure of samples to the aerobic environment during plating was held to less than 30min. Plates were counted after a 48h anaerobic incubation (37 degrees C). The species tested included Bacteroides fragilis (2), B. distasonis, B. thetaiotaomicron, Fusobacterium nucleatum, F. varium, Prevotella melaninogenica, Clostridium perfringens, Eubacterium lentum and Peptostreptococcus anaerobius (2). The activity of linezolid was compared to that of metronidazole and clindamycin, two standard anti-anaerobe agents. As expected, the control agents were very active in these assays. Metronidazole yielded log(10)CFU/mL reductions of 3.0 or greater for nine of ten strains; clindamycin yielded log(10)CFU/mL reductions of 2.0 or greater for six of 11 strains, and 3.0 or greater for three strains. Linezolid also produced significant in vitro killing in this model achieving log(10)CFU/mL reductions of 2.0 or greater for six of 11 strains, and 3.0 or greater for four strains. The profile of activity was similar to that of clindamycin indicating that additional developmental studies of linezolid with anaerobic bacteria are warranted.
