Oxazolidinone Moiety Research Articles

Asymmetric conjugate 1,6-addition of organocuprates to N-dienoyl oxazolidinones

A highly regioselective and diastereoselective conjugate 1,6-addition of organocuprates to N-dienoyl oxazolidinones to provide the 1,6-addition products, is described. These products have a β,γ-unsaturated olefin and a new asymmetric center at C(δ). The 1,6-addition products were obtained as a mixture of geometric isomers (E,Z), where its prevalence depends on reaction conditions and the type of Grignard reagent. This methodology can be carried out with small or voluminous alkyl Grignard reagents, aromatic or vinylic Grignard reagents, unlike other methodologies where there are difficulties with bulky Grignard reagents. It is the first paper describing a competition between geometric isomers (E, Z) into the 1,6- addition products depending on the employed reaction conditions. Chiral oxazolidinone moiety removal furnished chiral δ-substituted β,γ-unsaturated carboxylic acids.

Potent and specific antibiotic combination therapy against Clostridioides difficile.

Keratinicyclins and keratinimicins are recently discovered glycopeptide antibiotics. Keratinimicins show broad-spectrum activity against Gram-positive bacteria, while keratinicyclins form a new chemotype by virtue of an unusual oxazolidinone moiety and exhibit specific antibiosis against Clostridioides difficile. Here we report the mechanism of action of keratinicyclin B (KCB). We find that steric constraints preclude KCB from binding peptidoglycan termini. Instead, KCB inhibits C. difficile growth by binding wall teichoic acids (WTAs) and interfering with cell wall remodeling. A computational model, guided by biochemical studies, provides an image of the interaction of KCB with C. difficile WTAs and shows that the same H-bonding framework used by glycopeptide antibiotics to bind peptidoglycan termini is used by KCB for interacting with WTAs. Analysis of KCB in combination with vancomycin (VAN) shows highly synergistic and specific antimicrobial activity, and that nanomolar combinations of the two drugs are sufficient for complete growth inhibition of C. difficile, while leaving common commensal strains unaffected.

Optically Pure Calixarenyl Phosphine via Stereospecific Alkylation on Evans' Oxazolidinone Moiety.

A convenient protocol for the synthesis of 25,26,27-tribenzoyl-28-[((S)-1-diphenylphos- phanyl-propan-2-yl)oxy]-calix[4]arene via stereospecific methylation on Evans' oxazolidinone moiety was reported. According to the 13C NMR analysis of this phosphine, the calix[4]arene skeleton adopted a 1,3-alternate conformation. The latter conformation of the macrocycle and the (S)-chirality of the carbon atom bearing the methyl substituent were confirmed by a single-crystal X-ray diffraction study. After coordination of the phosphinated ligand to the dimeric [RuCl2(p-cymene)]2 organometallic precursor, the resulting arene-ruthenium complex was tested in the asymmetric reduction of acetophenone and alcohol was obtained with modest enantiomeric excess.

A short oxazolidine-2-one containing peptide forms supramolecular hydrogels under controlled conditions.

Low-molecular-weight hydrogels are made of a small percentage of small organic molecules dispersed in an aqueous medium, which may aggregate in several manners using different methods. However, often the organic gelator in water has poor solubility, so the addition of a solubilising agent is required. In the case of acidic gelators, this mainly consists of the addition of a strong base, that is sodium hydroxide, that deprotonates the acidic moiety, so the gelator molecules become more soluble and tend to assemble into micelles, forming a dispersion. Some gelators, however, are sensitive to the harsh pH and get hydrolysed. This is the case of some molecules presenting carbamates in their features, like Fmoc-protected or oxazolidinone-containing peptides. In this paper, we present a valid alternative to sodium hydroxide, by dissolving a tripeptide containing an oxazolidinone moiety in a phosphate buffer (PB) medium at pH 7.4. The results obtained with the NaOH dissolution are compared with the ones with PB, as both methods present advantages and drawbacks. The use of NaOH produces transparent but weak hydrogels, as it exposes the gelator to harsh conditions that end up in its partial hydrolysis, which is more pronounced at high concentrations (≥10 mM). Using PB to dissolve the gelator, this problem is completely avoided as no hydrolysis product has been detected in the hydrogels, which are very stiff although more opaque. By tuning the preparation conditions, we can obtain a wide variety of hydrogels, with the properties required by the final application.

Optical analysis of pure calixarenes and

Eight new optically pure calixarenyl derivatives, in which their lower rims were substituted with Evans oxazolidinone or pyranose moieties, were desbribed. All macrocycles were fully characterized by NMR spectroscopy, optical rotation and elemental analysis. Introduction of chiral auxiliaries reduced the symmetry of the macrocycle as observed by NMR. Stereospecific alkylation on the Evans oxazolidinone moiety allowed the asymmetric introduction of a methyl substituent near a phenolic position of the marocylcle.

Synthesis of optically pure calix[4]arenes derived from Evans oxazolidinone and/or pyranose

Eight new optically pure calixarene derivatives, in which their lower rims were substituted with Evans oxazolidinone or pyranose moieties, are described. All macrocycles were fully characterized by NMR spectroscopy, optical rotation, and elemental analysis. The introduction of chiral auxiliaries reduced the symmetry of the macrocycle as observed by NMR. Stereospecific alkylation on the Evans oxazolidinone moiety allowed the asymmetric introduction of a methyl substituent near a phenolic position of the macrocycle.

B-Cl-B]+ Cations: Chloroborane Masked Chiral Borenium Ions.

A tricoordinate borenium ion has received considerable attention in recent years for its applications in Lewis acid catalysis. Over the years, asymmetric catalysis mediated by a chiral borenium ion has also been developed. To stabilize the electron-deficient boron atom, a series of chloroborane masked borenium ions featuring the symmetrical [B-Cl-B]+ linkage are prepared and utilized as the catalyst for the enantioselective Diels-Alder cycloaddition of cyclopentadiene and 2,2,2-trifluoroethyl acrylate. The presence of a Cp* ligand is critical in realizing the cyclic diboron compounds, and the stability of the resulting [B-Cl-B]+ cation is dependent on the steric bulkiness of the oxazolidinone moiety. The stereoselectivity of the Diels-Alder cycloaddition is controlled by the substituents of the chiral oxazolidinone ligand and could be further improved via the coordination of SnCl4 at the bridging chloride of the [B-Cl-B]+ cation.

Synthesis of multifunctional 4-hydroxymethyl 2-oxazolidinones from glycidyl carbamate derivatives catalyzed by bicyclic guanidine

4-Hydroxymethyl 2-oxazolidinones have been successfully synthesized under mild conditions by the intramolecular cyclization of glycidyl carbamate derivatives with a bicyclic guanidine as the efficient catalyst. This reaction system, which is also applicable to the multifunctional compounds, can provide bi- and tri-functional alcohols having oxazolidinone moieties.

Anti-progressive Effects of a Series of Glycinyl and Alaninyl Triazolyl-oxazolidinones on Kelly Neuroblastoma Cell Line.

Neuroblastoma (NB), the most common extracranial malignant childhood tumor accounts for about 15% of cancer-related deaths in children. Despite the intensive treatment of patients with high-risk scarification of NB, clinical outcomes indicate tumor recurrence greater than 50% and late severe adverse effects. Oxazolidinones are 5-membered heterocyclic compounds with antibacterial activity against resistant bacterial strains. Structural modifications around the oxazolidinone moiety have resulted in derivatives with anti-cancer properties against proliferation, motility, and invasion of breast cancer cells. This study aimed to examine the anti-cancer potential of novel oxazolidinones against a model of a neuroblastoma cell line. Newly synthesized and characterized triazolyl-oxazolidinone derivatives were incubated with neuroblastoma Kelly cells. The anti-proliferation and anti-progression effects of the compounds were evaluated by MTT, and adhesion with migration assays. The 5-nitrofuroyl glycinyl-oxazolidinone containing 4-methyltriazolyl group demonstrated the most potent activity with an IC50=6.52 μM. Furthermore, the D-isomer of 5-nitrothiophenecarbonyl alaninyl containing derivative reduced the adhesion to fibronectin by 56.34%, while the D-isomer of 5-nitrofuroyl alaninyl derivative reduced the migration of Kelly cells by 29.14%. The presence of the 4-methyltriazolyl moiety seems to enhance the anti-proliferative property of triazolyl-oxazolidinone derivatives, as demonstrated by PH-145. There is little or no effect of the stereochemistry of the alanine side-chain on the antiproliferative effect, as demonstrated by the 5-nitrofuroyl D- and L-alaninyl containing derivatives with similar IC50 values. The observed differences in the inhibition of adhesion and migration by the oxazolidinones on Kelly cells provide a new therapeutic approach that needs further investigation.

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.

Diastereoselective conjugate addition of organocuprates to N-[4-(Dibenzylaminobutenoyl)]oxazolidinone. Synthesis of chiral β-substituted γ-aminoacids

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a γ-nitrogen atom is present into α,β-unsaturated system is described. The reaction gave syn-products in moderate yields and high diastereomeric ratios. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral β-substituted γ -amino acids.

Structural basis of translation inhibition by cadazolid, a novel quinoxolidinone antibiotic

Oxazolidinones are synthetic antibiotics used for treatment of infections caused by Gram-positive bacteria. They target the bacterial protein synthesis machinery by binding to the peptidyl transferase centre (PTC) of the ribosome and interfering with the peptidyl transferase reaction. Cadazolid is the first member of quinoxolidinone antibiotics, which are characterized by combining the pharmacophores of oxazolidinones and fluoroquinolones, and it is evaluated for treatment of Clostridium difficile gastrointestinal infections that frequently occur in hospitalized patients. In vitro protein synthesis inhibition by cadazolid was shown in Escherichia coli and Staphylococcus aureus, including an isolate resistant against linezolid, the prototypical oxazolidinone antibiotic. To better understand the mechanism of inhibition, we determined a 3.0 Å cryo-electron microscopy structure of cadazolid bound to the E. coli ribosome in complex with mRNA and initiator tRNA. Here we show that cadazolid binds with its oxazolidinone moiety in a binding pocket in close vicinity of the PTC as observed previously for linezolid, and that it extends its unique fluoroquinolone moiety towards the A-site of the PTC. In this position, the drug inhibits protein synthesis by interfering with the binding of tRNA to the A-site, suggesting that its chemical features also can enable the inhibition of linezolid-resistant strains.

Succinimidyl (3-[(benzyloxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl)acetate on a triazole-bonded phase for the separation of dl-amino-acid enantiomers and the mass-spectrometric determination of chiral amino acids in rat plasma

Changes in the levels of amino-acid enantiomers are associated with some serious diseases; consequently, amino acid monitoring in peripheral blood can be used to diagnose and predict the onset of disease. Herein, we report the design and synthesis of a new chiral derivatization reagent, namely succinimidyl (4S)-(3-[(benzyloxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl)acetate ((S)-COXA-OSu), for the separation of dl-amino-acid enantiomers. The usefulness of (S)-COXA-OSu was examined as a derivatization reagent for LC-MS/MS following certification of its total optical purity (>99%). The enantiomeric separations of amino-acid derivatives tagged with the reagent were examined using a triazole-bonded phase. (S)-COXA-OSu enabled the simultaneous enantiomeric separation of more than 40 α-amino acids. (S)-COXA-amino-acid derivatives were efficiently converted into their product ions, from which formaldehyde (CH2O) was eliminated [M-30] from the oxazolidinone moiety of COXA by collision-induced dissociation during LC-MS/MS. Limits of detection were in the 0.0138–0.518 pmol/injection range. For precise and accurate quantitation, we synthesized and used a stable-isotope-labeled (S)-COXA-OSu that was used as an internal standard in LC-MS/MS-determination experiments. Finally, changes in plasma amino-acid levels in rats, following administration of S-methyl-l-cysteine, an alanine-serine-cysteine transporter-1 (Asc-1) inhibitor, were successfully detected by LC-MS/MS using (S)-COXA-OSu.

Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties.

Novel representatives of the important group of biologically-active, dehydroabietic acid-bearing oxazolidinone moiety were synthesized to explore more efficacious and less toxic antitumor agents. Structures of all the newly target molecules were confirmed by IR, 1H-NMR, 13C-NMR, and HR-MS. The inhibitory activities of these compounds against different human cancer cell lines (MGC-803, CNE-2, SK-OV-3, NCI-H460) and human normal liver cell line LO2 were evaluated and compared with the commercial anticancer drug cisplatin, using standard MTT (methyl thiazolytetrazolium) assay in vitro. The pharmacological screening results revealed that most of the hybrids showed significantly improved antiproliferative activities over dehydroabietic acid and that some displayed better inhibitory activities compared to cisplatin. In particular, compound 4j exhibited promising cytotoxicity with IC50 values ranging from 3.82 to 17.76 µM against all the test cell lines and displayed very weak cytotoxicity (IC50 > 100 µM) on normal cells, showing good selectivity between normal and malignant cells. Furthermore, the action mechanism of the representative compound 4j was preliminarily investigated by Annexin-V/PI dual staining, Hoechst 33258 staining, which indicated that the compound can induce cell apoptosis in MGC-803 cells in a dose-dependent manner and arrest the cell cycle in G1 phase. Therefore, 4j may be further exploited as a novel pharmacophore model for the development of anticancer agents.

Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified

The current study deals with chemometric modelling strategies (Naïve Bayes classification, hologram-based quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)) to explore the important features of hydroxylamine derivatives for exerting potent human immunodeficiency virus-1 (HIV-1) protease inhibition. Depending on the statistically validated reliable and robust quantitative structure–activity relationship (QSAR) models, important and crucial structural features have been identified that may be responsible for enhancing the activity profile of these hydroxylamine compounds. Arylsulfonamide function along with methoxy or fluoro substitution is important for enhancing activity. Bulky steric substitution at the sulfonamide nitrogen disfavours activity whereas smaller hydrophobic substitution at the same position is found to be favourable. Apart from the crucial oxazolidinone moiety, pyrrolidine, cyclic urea and methyl ester functions are also responsible for increasing the HIV-1 protease inhibitory profile. Observations derived from these modelling studies may be utilized further in designing promising HIV-1 protease inhibitors of this class.

A new class of oxazolidinone- and phthalimide-based oxidation dye couplers and their effect on azomethine dye color

In the study of the effects of auxochromes on azomethine dye color, an oxazolidinone ring in the acceptor portion of the dye was useful both as a masking group for preparation of the electron-donating hydroxyethyl group, and as an electron-withdrawing auxochrome. In the case of m-aminophenol derivatives coupled with p-phenylenediamine, there was a 15 nm bathochromic shift relative to the parent azomethine of the series (PPD-MAP)3 and a 30 nm bathochromic shift relative to the azomethine formed from PPD and AHT, which contains an electron-donating group. However, unlike many electron-withdrawing groups, the oxazolidinone group does not significantly slow the rate of oxidative coupling of the MAP derivative with the primary intermediate to form the azomethine dye; it was about 70% of that for PPD with AHT, making the oxazolidinone-containing MAP a potentially effective oxidation dye intermediate. The effect on color of an oxazolidinone moiety in the acceptor portion of an azomethine formed with a 4,5-diaminopyrazole as the primary intermediate was similar in the magnitude of the bathochromic shift. Finally, including an auxochrome (phthalimide) that is electron-withdrawing in the acceptor portion of the azomethine, but which has decreased overlap with the π-system of the chromophore due to twisting out of plane caused by steric interactions, results in a significant hypsochromic shift.

Enantioselective allylic alkylation of stereodefined polysubstituted copper enolates as an entry to acyclic quaternary carbon stereocentres.

A sequence of regio- and stereoselective carbometalation followed by oxidation of ynamides leads to stereodefined fully substituted enolates that subsequently react with various functionalized allyl bromide reagents to provide the expected products possessing an enantiomerically pure quaternary carbon stereocentre in the α-position to the carbonyl group in excellent yields and enantiomeric ratios after cleavage of the oxazolidinone moiety. Three new bonds are formed in a single-pot operation.

ChemInform Abstract: ′Syn‐effect′ in the Diastereoselective Alkylation of 3‐[(E)‐α,β‐Unsaturated‐γ‐substituted] ‐N‐acyloxazolidinones.

Abstract Synthetic methods for the formation of alkenes usually produce the E-alkene because it is more stable. However, in isomerization reaction (double bond migration) that takes place in α, β−unsaturated carbonyl compounds, when these carbonyl compounds are exposed to strong bases, furnish Z-alkenes highly stereoselective depending on the γ-substituent in the α, β-unsaturated carbonyl. This stereoselectivity can be attributed to the known Syn-effect. The synthetic value of this methodology is the achievement of chiral alcohol bearing an electron rich Z-alkene, as well as substituted, which was accomplished via removal of the oxazolidinone moiety under treatment with NaBH4, THF-H2O.

Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation.

A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.

‘Syn-effect’ in the diastereoselective alkylation of 3-[(E)-α,β-unsaturated-γ-substituted]-N-acyloxazolidinones

Synthetic methods for the formation of alkenes usually produce the E-alkene because it is more stable. However, in isomerization reaction (double bond migration) that takes place in α, β−unsaturated carbonyl compounds, when these carbonyl compounds are exposed to strong bases, furnish Z-alkenes highly stereoselective depending on the γ-substituent in the α, β-unsaturated carbonyl. This stereoselectivity can be attributed to the known Syn-effect. The synthetic value of this methodology is the achievement of chiral alcohol bearing an electron rich Z-alkene, as well as substituted, which was accomplished via removal of the oxazolidinone moiety under treatment with NaBH4, THF-H2O.