Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring.

Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative eperezolid 3. As part of an investigation of the structure-activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values

Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones.

A series of conformationally restricted, [6,5,5] and [6,6,5] tricyclic fused oxazolidinones were synthesized and tested for antibacterial activity. Several compounds in the trans-[6,5,5] series demonstrated potent in vitro and in vivo activity. This work provides valuable information regarding the preferred conformational orientation of the oxazolidinones at the binding site.

Oxazolidinone antibacterial agents: development of the clinical candidates eperezolid and linezolid.

Antimicrobial resistance is a significant nosocomial problem and is of increasing importance in community-acquired infections. One approach for overcoming resistance is the discovery and development of agents with new mechanisms of action. The oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. Eperezolid and linezolid are two novel analogues that have demonstrated a variety of positive attributes. These agents inhibit many clinically-significant bacterial species both in vitro and in animal models of human infection. Furthermore they have oral bioavailability, and are well tolerated in humans at doses which produce plasma concentrations in excess of the levels predicted to be necessary for efficacy. In this review, we discuss the key information from the literature that supports the Phase II development of linezolid.

In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections.

The Upjohn oxazolidinones, U-100592 and U-100766, are orally bioavailable synthetic antimicrobial agents with spectra of activity against antibiotic-susceptible and -resistant gram-positive pathogens. In several mouse models of methicillin-resistant Staphylococcus aureus infection, U-100592 and U-100766 yielded oral 50% effective doses (ED50) ranging from 1.9 to 8.0 mg/kg of body weight, which compared favorably with vancomycin subcutaneous ED50 values of 1.1 to 4.4 mg/kg. Similarly, both compounds were active versus a Staphylococcus epidermidis experimental systemic infection. U-100592 and U-100766 effectively cured an Enterococcus faecalis systemic infection, with ED50 values of 1.3 and 10.0 mg/kg, and versus a vancomycin-resistant Enterococcus faecium infection in immunocompromised mice, both drugs effected cures at 12.5 and 24.0 mg/kg. Both compounds were exceptionally active in vivo against penicillin- and cephalosporin-resistant Streptococcus pneumoniae, with ED50 values ranging from 1.2 to 11.7 mg/kg in systemic infection models. In soft tissue infection models with S. aureus and E. faecalis, both compounds exhibited acceptable curative activities in the range of 11.0 to 39.0 mg/kg. U-100766 was also very active versus the Bacteroides fragilis soft tissue infection model (ED50 = 46.3 mg/kg). In combination-therapy studies, both U-100592 and U-100766 were indifferent or additive in vivo against a monomicrobic S. aureus infection in combination with other antibiotics active against gram-positive bacteria and combined as readily as vancomycin with gentamicin in the treatment of a polymicrobic S. aureus-Escherichia coli infection. U-100592 and U-100766 are potent oxazolidinones active against antibiotic-susceptible and -resistant gram-positive pathogens in experimental systemic and soft tissue infections.

In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.

Oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. U-100592 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and U-100766 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide are novel oxazolidinone analogs from a directed chemical modification program. MICs were determined for a variety of bacterial clinical isolates; the respective MICs of U-100592 and U-100766 at which 90% of isolates are inhibited were as follows: methicillin-susceptible Staphylococcus aureus, 4 and 4 micrograms/ml; methicillin-resistant S. aureus, 4 and 4 micrograms/ml; methicillin-susceptible Staphylococcus epidermidis, 2 and 2 micrograms/ml; methicillin-resistant S. epidermidis, 1 and 2 micrograms/ml; Enterococcus faecalis, 2 and 4 micrograms/ml; Enterococcus faecium, 2 and 4 micrograms/ml; Streptococcus pyogenes, 1 and 2 micrograms/ml; Streptococcus pneumoniae, 0.50 and 1 microgram/ml; Corynebacterium spp., 0.50 and 0.50 micrograms/ml; Moraxella catarrhalis, 4 and 4 micrograms/ml; Listeria monocytogenes, 8 and 2 micrograms/ml; and Bacteroides fragilis, 16 and 4 micrograms/ml. Most strains of Mycobacterium tuberculosis and the gram-positive anaerobes were inhibited in the range of 0.50 to 2 micrograms/ml. Enterococcal strains resistant to vancomycin (VanA, VanB, and VanC resistance phenotypes), pneumococcal strains resistant to penicillin, and M. tuberculosis strains resistant to common antitubercular agents (isoniazid, streptomycin, rifampin, ethionamide, and ethambutol) were not cross-resistant to the oxazolidinones. The presence of 10, 20, and 40% pooled human serum did not affect the antibacterial activities of the oxazolidinones. Time-kill studies demonstrated a bacteriostatic effect of the analogs against staphylococci and enterococci but a bactericidal effect against streptococci. The spontaneous mutation frequencies of S. aureus ATCC 29213 were <3.8 x 10(-10) and <8 x 10(-11) for U-100592 and U-100766, respectively. Serial transfer of three staphylococcal and two enterococcal strains on drug gradient plates produced no evidence of rapid resistance development. Thus, these new oxazolidinone analogs demonstrated in vitro antibacterial activities against a variety of clinically important human pathogens.

Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections.

Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.

Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity.

During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.

N-acyl 3-alkylidenyl- and 3-alkyl azetidin-2-ones: a new class of monocyclic beta-lactam antibacterial agents. 1. Structure-activity relationships of 3-isopropylidene and 3-isopropyl analogs.

The synthesis and antibacterial activity of a series of N-acyl 3-isopropylidenyl- and 3-isopropyl 2-azetidinones having potent in vitro antibacterial activity, particularly against anaerobic organisms, is described. A distinguishing structural feature of these compounds is the lack of any ionizable moiety appendant to the lactam nitrogen.