Oxazolidinone Structure–Activity Relationships Leading to Linezolid

Abstract

The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings. A number of solutions to the problem of bacterial resistance are possible. The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes. Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity. Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise. Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs. This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.

Streptogramins, Oxazolidinones, and Other Inhibitors of Bacterial Protein Synthesis

“…68,69 While these compounds showed good antibacterial activity against Gram-positive bacteria such as Staphylococci, Streptococci, and Enterococci, 68 the compound class was not pursued as a result of toxicity issues in animals studies. 70 Scientists at Pharmacia subsequently found that a structure-toxicity relationship could be established for the oxazolidinones and initiated a campaign to develop these compounds as novel antibacterial agents (historically reviewed in ref 70).…”

“…The details of this SAR program have recently been reviewed. 70 The outcome of this drug discovery program is the antibiotic linezolid (Figure 13), which received FDA approval in 2000 and is marketed under the trade name Zyvox. 76 Linezolid is active both in oral and injectable forms and is indicated for the treatment of a variety of infections caused by Gram-positive bacteria.…”

An efficient access to functionally substituted 1,3-oxazolidin-2-ones via cyclization of 1-alkylamino- and 1-arylamino-3-[2-(vinyloxy)ethoxy)]propan-2-ols with dimethyl carbonate

“…[1][2][3] Among oxazolidin-2-ones derivatives there are new synthetic antibacterial agents active against gram-positive microorganisms, including multiple-antibiotic resistant strains (eg. linezolid which has been awarded the 2003 Prix Galien in Germany, as the prominent innovative drug), [4][5][6] as well as pharmaceuticals with different pharmacological activities e.g. drugs for prevention and treatment of heart disorders, antithrombotics 7,8 and anti-tumor remedies, 9,10 antidepressants.…”

Energyless CO₂ Absorption, Generation, and Fixation Using Atmospheric CO₂

“…Many types of pharmacologically active compounds containing oxazolidinone frameworks have been reported. 48,49) When propargylamine and its derivatives bearing alkyl or phenyl groups 8 were added to a Au or Ag catalyst in MeOH under atmospheric conditions, no desired product 9 was observed (Fig. 3, Eq.…”