Identification of Phenylisoxazolines as Novel and Viable Antibacterial Agents Active against Gram-Positive Pathogens

Abstract

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.

Inhibition of Mammalian Mitochondrial Protein Synthesis by Oxazolidinones

“…The development of new oxazolidinone compounds as antibacterials (6,16,18,19,29,31,37,38) and as monoamine oxidase A inhibitors (13,27) remains an active area of research involving several companies. However, since the results of the study reported here indicate that oxazolidinones that are highly potent as antibacterials are likely to be potent inhibitors of mitochondrial protein synthesis and may display increased toxicity in animals, a strong case can be made for evaluating the effects on mitochondria during the development of drugs of the oxazolidinone class.…”

“…Dosedependent and reversible bone marrow suppression has been noted as a side effect of treatment with linezolid (17,22), consistent with inhibition of mitochondrial protein synthesis, as has been noted for chloramphenicol (15,39). Pharmacia (now Pfizer) has synthesized newer oxazolidinones with increased antibiotic potency, in particular ones that would be effective against gram-negative bacteria (6,16). While linezolid was essentially nontoxic in a rat toxicity assay (100 mg/kg of body weight, twice daily for 30 days) (10), as noted herein, some of the newer compounds were significantly more toxic, leading to rat deaths within the 30-day assay period.…”

Green Organocatalytic Oxidative Methods using Activated Ketones

“…Notably,c ompounds bearing the isoxazoline moiety have been described to exhibit impressive anti-inflammatory, [96] antifungal, [97] antimicrobial, [98] and antibacterial activity. [99] Lactones are important structural motifs that are encountered in antibiotic and antitumor agents, agrochemicals, flavor components, and polymer production. [100] Ar ecent contribution to this area Scheme23.…”

Library of 1,4-Disubstituted 1,2,3-Triazole Analogs of Oxazolidinone RNA-Binding Agents

“…Several isosteric analogs to the oxazolidinone ring have been reported with varying degrees of success 5. These include isoxazoline (removes the carbonyl and introduces a C=N double bond),6 benzisoxazolinones (C=C double bond, replacement of sp3 carbon with an N),7 and pyrroles (completely flat aromatic ring system) 7. Of these bioisosteric analogs of the oxazolidinone, only the isoxazoline and the benzisoxazolinone had activity similar to the parent compound.…”