Oxazolidinone Derivatives Research Articles

Stereospecific synthesis of a dl- gala-aminoquercitol derivative

A new aminoquercitol derivative was synthesized starting from 1,4-cyclohexadiene. Photooxygenation of cyclohexa-1,4-diene afforded anti-2,3-dioxabicyclo[2.2.2]oct-7-en-5-yl hydroperoxide as the main product. The formed hydroperoxy endoperoxide was reduced with LiAlH 4 to produce anti-2,3-dioxabicyclo[2.2.2]oct-7-en-5-ol. Protection of alcohol with acetyl chloride followed by reduction of the endoperoxide with thiourea, and then palladium-catalyzed ionization/cyclization reaction gave an oxazolidinone derivative. Hydrolysis of the oxazolidinone ring and acetylation gave an amino compound. Oxidation of the double bond in the amino compound with OsO 4 followed by acetylation gave the amino tetraacetate and removal of the acetate groups furnished the desired aminoquercitol whose exact configuration was determined by X-ray diffraction analysis.

An enantioselective total synthesis of ( S)-(−)-licochalcone E: determination of the absolute configuration

The absolute configuration of (−)-licochalcone E ( 1) was determined to be ( S) via the first enantioselective total synthesis of the compound. The chirality in ( S)-(−)-licochalcone E ( 1) was installed by asymmetric methylation of the Evans' oxazolidinone derivatives.

Synthesis of a new class of aminocyclitol analogues with the conduramine D-2 configuration.

A new class of aminocyclitol derivatives with the bicyclo[4.2.0]octane skeleton was synthesized starting from cyclooctatetraene. Photooxygenation of trans-7,8-diacetoxy- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-diene afforded the bicyclic endoperoxides. Reduction of the latter with thiourea followed by a Pd(0) catalyzed ionization/cyclization reaction gave the corresponding oxazolidinone derivatives. Oxidation of the double bond with KMnO4 or OsO4 followed by acetylation gave the acetate derivatives, the exact configuration of which was determined by spectroscopic methods. Hydrolysis of the oxazolidinone rings and removal of the acetate groups furnished the desired aminocyclitols.

The Oxazolidinone Derivative Locostatin Induces Cytokine Appeasement

Damaging inflammation arising from autoimmune pathology and septic responses results in severe cases of disease. In both instances, anti-inflammatory compounds are used to limit the excessive or deregulated cytokine responses. We used a model of robust T cell stimulation to identify new proteins involved in triggering a cytokine storm. A comparative proteomic mining approach revealed the differential mapping of Raf kinase inhibitory protein after T cell recall in vivo. Treatment with locostatin, an Raf kinase inhibitory protein inhibitor, induced T cell anergy by blocking cytokine production after Ag recall. This was associated with a reduction in Erk phosphorylation. Importantly, in vivo treatment with locostatin profoundly inhibited TNF-alpha production upon triggering the Ag-specific T cells. This effect was not limited to a murine model because locostatin efficiently inhibited cytokine secretion by human lymphocytes. Therefore, locostatin should be a useful therapeutic to control inflammation, sepsis, and autoimmune diseases.

Reaction of reductively activated mitomycin C with aqueous bicarbonate: Isolation and characterization of an oxazolidinone derivative of cis-1-hydroxy-2,7-diaminomitosene

The reductive activation of mitomycin C in aqueous bicarbonate buffer resulted in the formation of a previously unknown compound, characterized as an oxazolidinone derivative of cis-1-hydroxy-2,7-diaminomitosene. This compound is the result of a cyclization reaction of bicarbonate with the aziridine ring of aziridinomitosene, and was observed at bicarbonate concentrations close to those present in physiological plasma.

11C]SL25.1188, a new reversible radioligand to study the monoamine oxidase type B with PET: Preclinical characterisation in nonhuman primate

[(11)C]SL-25.1188 [(S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-benzo[d]isoxazol-3-yl]-oxazolidin-2-one], an oxazolidinone derivative, was characterized in baboons as a radioligand for the in vivo visualization of MAO-B using positron emission tomography (PET). After i.v. injection, [(11)C]SL25.1188 presented a rapid phase of distribution in blood (about 5 min), followed by a T(1/2) elimination of 85 +/- 14 min. Plasma metabolism analysis showed that [(11)C]SL25.1188 is stable in vivo at least for 30 min. Brain uptake was rapid with the highest one observed in the striatum and thalamus, and the lowest in the pons. Calculated distribution volumes (V(T)) were as follows: striatum = 10.3, thalamus = 10.9, hippocampus = 8.9, temporal cortex = 7.7, occipital cortex = 7.2, parietal cortex = 7.4, frontal cortex = 7.4, white matter = 7.4, and pons = 6.1. Pretreatment with deprenyl (2 mg/kg, i.v.) or lazabemide (0.5 mg/kg, i.v.) reduced V(T) values in all brain areas up to 50%. In displacement experiments, injection of SL25.1188 or deprenyl (1 and 2 mg/kg, i.v., respectively) strongly reduced the specific uptake of [(11)C]SL25.1188 in all brain areas (85-100%), while a lesser displacement was observed with lazabemide (0.5 mg/kg, i.v.) (55-70% of specific binding depending on the brain area). Therefore, [(11)C]SL25.1188 is characterized in vivo by reversible binding, high brain uptake and very slow plasma metabolism, strongly suggesting that this radioligand is a potent tool for the in vivo study of brain MAO-B.

Synthesis and Antibacterial Activity of a Series of α‐Substituted Acetylpiperazinyl Oxazolidinones

A series of oxazolidinone derivatives with alpha-substituted acetylpiperazinyl groups were prepared. Their in vitro antibacterial activities were studied against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. The compounds with chloroacetyl-piperazinyl or dichloroacetyl-piperazinyl group were found to have superior antibacterial activities to linezolid against most of tested Gram-positive pathogens. The compounds with propionylpiperaziny or fluoroacetylpiperazinyl group were found to have comparable antibacterial activities with linezolid. However, the replacement of phenyl ring of the compounds with pyridine ring resulted in the significant loss of antibacterial activity.

ChemInform Abstract: Stereoselective Syntheses of (E)‐α,β‐Didehydroamino Acid and Peptide Containing Its Residue Utilizing Oxazolidinone Derivative

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Silver-catalyzed Preparation of Oxazolidinones from Carbon Dioxide and Propargylic Amines

Abstract The silver-catalyzed carbon dioxide incorporation reaction into various propargylic amines proceeded under mild reaction conditions to obtain the corresponding oxazolidinone derivatives in high to excellent yields. The geometry of the C–C double bond in product was confirmed to be the Z isomer by X-ray analysis.

Stereoselective Syntheses of (E)-α,β-Didehydroamino Acid and Peptide Containing Its Residue Utilizing Oxazolidinone Derivative

Abstract Reaction of methyl N-Boc-N-phenoxycarbonylglycinate with various aldehydes afforded the corresponding cis-4,5-oxazolidinone derivatives, which were effectively converted to (E)-α,β-didehydroamino acids by means of a base. Furthermore, N-deprotection of the oxazolidinone derivatives and subsequent coupling reaction with Boc-amino acid furnished the corresponding dipeptides, which were transformed to dipeptide containing α,β-didehydroamino acid with high E selectivity.

Therapeutic options for the treatment of infections with multiresistant grampositive bacteria in oncological patients

Infections with highly resistant grampositive bacteria are a major threat to the patients with underlying malignant diseases and due to more aggressive treatment strategies the incidence of these infections increased over the past years. For many years, glycopeptides such as vancomycin, have been the standard treatment for methicillin-resistant S. aureus (MRSA) and ampicillin-resistant enterococci. However, the clinical use of vancomycin may be limited by the adverse effects like poor tissue penetration and the emergence of vancomycin-resistant strains such as vancomycin-resistant enterococci and staphylococci. Thus, in recent years, new antimicrobial agents have been introduced into clinical praxis or are under investigation. This review summarizes current clinical data on novel therapeutics such as linezolid, tigecycline and daptomycin as well as investigational new drugs. Linezolid, an oxazolidinone derivative, has proven clinical activity only against infections with grampositive bacteria including vancomycin-resistant rods. Tigecycline is a tetracycline derivative with a very broad antimicrobial spectrum including multiresistant grampositive strains. Daptomycin, belonging to a new class of cyclic lipopeptide antibiotics, is approved for the treatment of skin and skin-structure infections, bactermia and endocarditis with grampositive bacteria. However, only limited data exist on the clinical use of tigecycline and daptomycin in oncological patients. In the near future, novel cephalosporins and carbapenems with activity against MRSA as well as new semisynthetic glycopeptides will extend our therapeutic possibilities in the treatment of infections by multiresistant grampositive bacteria.

A convenient synthesis of oxazolidinone derivatives linezolid and eperezolid from (S)‐glyceraldehyde acetonide

AbstractA new convenient method for the synthesis of oxazolidinone antibacterials Linezolid and Eperezolid from readily available (S)‐glyceraldehyde acetonide was developed. The key steps include reductive amination of arylamine and (S)‐glyceraldehyde acetonide in the presence of NaBH4 and 4 Å sieve, followed by hydrolysis and regioselective cyclization. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:316–319, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20435

Expeditious, large scale preparation of ethyl ( R)-5-methyl-3-oxo octanoate via a cross Claisen reaction between N-acyl oxazolidinone derivatives and the magnesium enolate of potassium ethyl malonate

A new and efficient method for the direct conversion of N-acyl oxazolidinones to a β-keto ester is disclosed. The one-pot transformation is effected by the utilization of an excess of Lewis acid along with base and potassium ethyl malonate. This methodology has been applied to the large scale preparation of ethyl ( R)-5-methyl-3-oxooctanoate.

New oxazolidinone derivatives as antibacterial agents with improved activity

Background: Considerable efforts have been made in order to find new oxazolidinone-based antibacterial agents with improved biological profile. Objective: The purpose of this review is to highlight application patents on oxazolidinone-based antibacterial agents that appeared from mid-2004 to the end of 2006. Methods: The major actors in this field were private companies that have done an intense research activity, in order to individuate the most important features responsible for the activity, starting from the results previously obtained by Pharmacia & Upjohn. Results/conclusion: A huge number of oxazolidinone derivatives are presently under study and a lot of WO-PCT applications appeared during the last few years. Although these recent works show that significant goals could be reached, data reported in analyzed patent applications do not allow to assure exactly that in the near future one of these oxazolidinones could reach the market.

Direct Entry to Peptidyl Ketones via SmI2-Mediated C−C Bond Formation with Readily Accessible N-Peptidyl Oxazolidinones

In this work, a new method for the preparation of peptidyl ketones is presented employing a SmI(2)/H(2)O-mediated coupling of N-peptidyl oxazolidinones with electron-deficient alkenes. The requisite peptide imides were easily prepared by solution-phase peptide synthesis starting from an N-acyl oxazolidinone derivative of an amino acid. Importantly, they could be used directly in the C-C bond-forming step without the need for further functionalization. Coupling of these peptide derivatives with a second peptide possessing an N-terminal acryloyl group leads to ketomethylene isosteres of glycine-containing peptides. This method represents an alternative means for ligating two small peptides through a C-C bond-forming step.

Synthesis and characterization of chiral 1,2-diamines from 5-oxo-pyrrolidine-( S)-2-carboxylic acid

Unsymmetrical chiral secondary vicinal diamines were synthesized by applying a modified three-step reaction. The key step in this sequence is a primary amine mediated ring opening reaction of a diastereomeric oxazolidinone derivative. A possible mechanism for this step is described.

Structure—Antibacterial Activity of Arylcarbonyl‐ and Arylsulfonyl‐Piperazine 5‐Triazolylmethyl Oxazolidinones.

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Synthesis and antibacterial activity of novel oxazolidinones with methylene oxygen- and methylene sulfur-linked substituents at C5-position

Novel oxazolidinone derivatives of the lead compound RBx 8700, containing methylene oxygen- and methylene sulfur-linked substituents at the C5-position, were synthesized. Antibacterial screening of these compounds against a panel of resistant and susceptible Gram-positive and fastidious Gram-negative bacteria gave compounds 2 and 4 as new antibacterial agents.

Preferential Intramolecular Ring Closure of Aminoalcohols with Diethyl Carbonate to Oxazolidinones

The closure by cyclization with diethyl carbonate (EtO)(2)CO from aminoalcohols 1 as starting material can lead to the oxazolidinones 2a, b and 2c, respectively. In the reaction of trans-isomer (6) and (EtO)(2)CO, isolated products were also only 5-membered oxazolidinone derivative (7), containing its dehydrated derivative 8. The preferential formation of the 5-membered oxazolidinone ring system apparently indicated that this process (5-Exo-Trig ring closure) is more favorable than that of 6- or 7-membered ring derivative (3 or 9) by 6- or 7-Exo-Trig ring closure.

Structure–antibacterial activity of arylcarbonyl- and arylsulfonyl-piperazine 5-triazolylmethyl oxazolidinones

A series of novel arylcarbonyl- and arylsulfonyl-piperazinyl 5-triazolylmethyl oxazolidinones were synthesized and tested against a panel of Gram-positive and Gram-negative bacterial clinical isolates. The arylcarbonyl oxazolidinone derivatives showed strong in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria and were more active than the arylsufonyl derivatives. Substitution of varied electron-withdrawing and electron-donating groups on the phenyl ring in the arylcarbonyl series did not alter antibacterial activity significantly. However, in the arylsufonyl series, methyl substitution on the phenyl ring resulted in the loss of antibacterial activity. Antibacterial activity could not be directly correlated with the calculated partition coefficient (Clog P) values in this series of compounds.