Synthesis and SAR of novel oxazolidinones: Discovery of ranbezolid

“…Ranbezolid, an investigational oxazolidinone, showed excellent in vitro activity against gram-positive pathogens, especially methicillin-susceptible S. aureus and MRSA, and also against methicillin-susceptible Staphylococcus epidermidis and methicillin-resistant S. epidermidis (MRSE) (5,11,19,20). In addition, ranbezolid is the first oxazolidinone which showed similar activities against both gram-negative and gram-positive anaerobes (6,11).…”

mentioning

confidence: 99%

Mode of Action of Ranbezolid against Staphylococci and Structural Modeling Studies of Its Interaction with Ribosomes

Kalia¹,

Miglani²,

Purnapatre³

et al. 2009

Antimicrob Agents Chemother

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Oxazolidinones are known to inhibit protein biosynthesis and act against a wide spectrum of gram-positive bacteria. A new investigational oxazolidinone, ranbezolid, inhibited bacterial protein synthesis in Staphylococcus aureus and Staphylococcus epidermidis. In S. epidermidis, ranbezolid showed inhibition of cell wall and lipid synthesis and a dose-dependent effect on membrane integrity. A kill-kinetics study showed that ranbezolid was bactericidal against S. epidermidis. In vitro translation of the luciferase gene done using bacterial and mammalian ribosomes indicated that ranbezolid specifically inhibited the bacterial ribosome. Molecular modeling studies revealed that both linezolid and ranbezolid fit in similar manners the active site of ribosomes, with total scores, i.e., theoretical binding affinities after consensus, of 5.2 and 6.9, respectively. The nitrofuran ring in ranbezolid is extended toward C2507, G2583, and U2584, and the nitro group forms a hydrogen bond from the base of G2583. The interaction of ranbezolid with the bacterial ribosomes clearly helps to elucidate its potent activity against the target pathogen.

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“…Modification of this position has resulted in several compounds with improved profiles of activity. For example, Ranbezolid (RBX7644, 85) containing 2-substituted-5-nitrofuryl derivative on the piperazinyl C ring showed in vitro activity similar to that of Linezolid [87]. The compound was also efficacious in vivo, exhibited a favorable pharmacokinetic and safety profile and is currently undergoing clinical studies [88].…”

Section: B and C Ring Modificationsmentioning

confidence: 98%

“…These compounds (87)(88)(89)(90) A series of arylcarbonyl and arylsulfonyl oxazolidinones have also been synthesized and evaluated (91,92). Many of these compounds showed superior in vitro antibacterial activity for Gram-positive bacteria over Linezolid.…”

Section: B and C Ring Modificationsmentioning

confidence: 98%

Synthesis and Antibacterial Properties of Oxazolidinones and Oxazinanones

Wang¹

2008

AIAMC

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Oxazolidinones are important synthetic antibacterial agents useful for the treatment of multi antibiotic resistant Gram-positive bacterial infections. Since the launch of Linezolid, the first member of the oxazolidinone antibacterial family, there have been many studies directed towards structural optimization and the development of second generation oxazolidinones. The N-aryl 5-acetamido methyl oxazolidinone is the core structure for this class of antibacterial agents and the oxazolidinone component is essential for antibacterial activities. The chiral cyclic carbamate 5-hydroxymethyloxazolidin-2-one and 6-hydroxymethyl-[1,3]oxazinan-2-one are also important building blocks for synthesizing other biologically active compounds. Because of the importance of these compounds, many methods have been developed for their facile syntheses. In the first part of this paper, the synthesis of Linezolid and its analogs, as well as the preparation of the oxazolidinone core structures, will be reviewed. Secondly, recent developments in the area of oxazolidinone antibacterial agents including structure-activity relationships will be reviewed.

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Synthesis and SAR of novel oxazolidinones: Discovery of ranbezolid

Cited by 57 publications

References 8 publications

3D QSAR analysis of oxazolidinone antibacterials: can we predict?

3D QSAR analysis of oxazolidinone antibacterials: can we predict?

Mode of Action of Ranbezolid against Staphylococci and Structural Modeling Studies of Its Interaction with Ribosomes

Synthesis and Antibacterial Properties of Oxazolidinones and Oxazinanones

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