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The given article describes the synthesis of 2-Oxazolidinone ring via proline catalyzed stereoselective α-aminoxylation of aldehyde. 2-Oxazolidinone ring is a common core structure during the synthesis of oxazolidinones class molecules. Using this simple, facile and efficient methodology, Linezolid and sutezolid were prepared using asymmetric catalysis. Selective α-aminoxylation was achieved on corresponding aldehyde with great enantiomeric excess to get intermediate (5) using catalytic amount of low cost proline. The oxazolidinone ring was then constructed on common intermediate (5) which was then further converted to Oxazolidinone class compounds like Sutezolid and Eperezolid. [ABSTRACT FROM AUTHOR]

The reaction conditions for an enantiospecific synthesis of various N-aryl-oxazolidinones from N-arylcarbamates and (R) or (S) epichlorohydrin were optimized. The N-aryl-oxazolidinones were applied to the synthesis of compounds of biological interest such as DuP 721, toloxatone and a linezolid analogue. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety. • Compound 10e exhibited a MIC value of 0.125 μg/mL against all tested bacteria. • The potency of compound 10e against LREF was 64-fold higher than that of linezolid. • Compound 10e was non-cytotoxic with an IC 50 value of 91.04 μM against HepG2 cell. Abstract Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a−6b. The preliminary study showed that compounds 7 , 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 µg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5 µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC 50 value of 91.04 μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium responsible for severe infections, and it is naturally resistant to many clinically approved antibiotic families. Oxazolidinone antibiotics are active against many Gram-positive bacteria, but are inactive against P. aeruginosa . Increasing the uptake of oxazolidinones through the bacterial envelope could lead to an increased antibiotic effect. Pyochelin is a siderophore of P. aeruginosa which delivers external iron to the bacterial cytoplasm and is a potential vector for the development of Trojan Horse oxazolidinone conjugates. Novel pyochelin-oxazolidinone conjugates were synthesized using an unexpectedly regioselective peptide coupling between an amine functionalized pyochelin and oxazolidinones functionalized with a terminal carboxylate. [ABSTRACT FROM AUTHOR]

The total synthesis of oxazolidinone-based pharmaceuticals, linezolid, tedizolid and rivaroxaban is reported. They are synthesized using a recently reported copper-catalyzed one-pot cyclization and arylation as the key step to construct the N-aryloxazolidinone core. Active pharmaceutical ingredients (API) were synthesized from a common synthetic pool of a simple protected amino alcohol in 22 %, 61 % and 40 % total synthesis yields, respectively. [ABSTRACT FROM AUTHOR]

In this work, for the first time we report complementary structural and spectral studies of linezolid and its synthetic precursors ( R)- N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methanol and ( R)- N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methyl azide employing solid-state nuclear magnetic resonance ( SS NMR) spectroscopy and electron ionization mass spectrometry. Each technique provides unique and specific set of information. Through high-resolution SS NMR using 13 C, 15 N, and 19 F as structural probes, we revealed dynamic molecular disorder in the crystal lattice for polymorphs II and III of linezolid, never reported before. Utilizing variable temperature 13 C cross-polarization magic-angle spinning technique, we proved that the disorder has a local character. Only morpholine residue of linezolid is under fast regime exchange at room temperature. This process slows down at a lower temperature and stopped at 213 K. The mass spectrometry revealed that chemical modification at oxazolidinone end of linezolid has a significant influence on fragmentation pathways of studied drug and its synthetic precursors. In particular, the compound that has azide group at the methyl substituent in the position C5 of the oxazolidinone ring is characterized by the most complicated fragmentation pattern, probably caused by thermal decomposition, which was taking place before ionization. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3883-3892, 2015 [ABSTRACT FROM AUTHOR]

[Display omitted] A new method was developed for the synthesis of Linezolid from commercially available (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one. Linezolid is an antibiotic belongs to the family of oxazolidinones, it is successfully synthesized through a new method which include Buchwald-Hartwig amination reaction and Gabriel amine synthesis as the key steps. The synthetic route is easy to perform and with high yield. This new method provides a huge possibility for the synthesis of new linezolid derivatives that may possibly tackle the problem of bacteria resistance to oxazolidinones. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to enhance cellular uptake of simplified analogs of Linezolid by their incorporation into suitable delivery devices in order to improve the antimicrobial activity of these novel synthesized oxazolidin-2-one derivatives. The oxazolidin-2-one derivatives were synthesized by developing a rather simple one-pot reaction starting from oxiranylmethanol and several primary amines. Three delivery devices were prepared by following different synthetic approaches, such as single-step free radical grafting, precipitation polymerization and nano-emulsion. Finally, the antimicrobial activity of the novel synthesized compounds, without any vehicle and after their incorporation into the delivery devices, was evaluated against Escherichia coli and Saccharomyces cerevisiae by performing time-kill analyses. The synthesized oxazolidinones exhibited modest antimicrobial activity against E. coli and S. cerevisiae (MIC 16μg/mL). A good activity was, instead, highlighted after their incorporation into the prepared delivery devices (lecithin-based nano-emulsion, poly(N-vinyl-pyrrolidone)-methacrylic acid grafted copolymer and spherical polymeric nanoparticles) (MIC≤4μg/mL). The incorporation into suitable vehicles, indeed, reduced by 4 times the normal MICs of the newly synthesized oxazolilidin-2-ones and represents an effective strategy to overcome cellular penetration constraints. [Copyright &y& Elsevier]

Abstract: A series of 1H-1,2,3-triazolyl piperazino oxazolidinone analogs with optionally varied glycinyl substitutions were synthesized and their antibacterial activity assessed against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria including clinical isolates. The N-aroyl- and N-heteroaroyl-glycinyl (MIC: 0.06–4 μg/ml) derivatives were more potent than the N-acylglycinyl (2–8 μg/ml) derivatives against all Gram-positive bacteria tested. Nitro substitution on aryl and heteroaryl rings significantly enhanced activity against Gram-positive bacteria, as noted with the 3,5-dinitrobenzoyl (6m and 6n) and 5-nitro-2-furoyl (6u and 6v) derivatives with MIC ranges of and 0.25–0.5 and 0.06–0.5 μg/ml, respectively. These nitro analogs also showed more potent extended activity against Moraxella catarrhalis, with MICs ranges of 0.25–1 μg/ml, compared to linezolid (MIC: 8 μg/ml). Hence, the presence of the N-aroyl and/or N-heteroaroyl glycinyl structural motifs as spacer group could significantly enhance the antibacterial activities of 1H-1,2,3-triazolyl oxazolidinone class of compounds. [Copyright &y& Elsevier]

Abstract: The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches – FLAP and Amber software – shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained. [Copyright &y& Elsevier]

Abstract: A number of linezolid-like oxazolidino-sulfonamides (7a–y and 8a–b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0–6.0 μg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 μg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented. [Copyright &y& Elsevier]

Abstract: A novel series of 5(R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl]oxazolidinones having various piperidine group were synthesized and evaluated antibacterial activity against clinically isolated resistant strains of Gram-positive and Gram-negative bacteria. The compound 12a having exo-cyanoethylidene group in the 4-position of piperidine ring was found to be two to threefold more potent than the linezolid against penicillin-resistant Staphylococcus pneumonia and Staphylococcus agalactiae, and also exhibited reduced MAO-B inhibitory activity. [Copyright &y& Elsevier]

A short, concise and efficient synthesis of Linezolid was accomplished through a convergent scheme utilizing either (S)-1-azido-3-chloropropan-2-yl chloroformate or (S)-1- phthalimido-3- chloropropan-2-yl chloroformate as a key starting material. The synthesis demonstrates utility of (S)-1-azido-3-chloropropan-2-yl chloroformate and/or (S)-1-phthalimido-3-chloropropan-2-yl chloroformate to facilitate the expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones and offers the possibility of accessing related 2-oxazolidinone members easily as well as making additional analogues of Linezolid. [ABSTRACT FROM AUTHOR]

This review covers the main aspects concerning the chemistry, the biological activity and the analytical determination of oxazolidinones, the only new class of synthetic antibiotics advanced in clinical use over the past 50 years. They are characterized by a chemical structure including the oxazolidone ring with the S configuration of substituent at C5, the acylaminomethyl group linked to C5 and the N-aryl substituent. The synthesis of oxazolidinones has gained increasing interest due to their unique mechanism of action that assures high antibiotic efficiency and low susceptibility to resistance mechanisms. Here, the main features of oxazolidinone antibiotics licensed or under development, such as Linezolid, Sutezolid, Eperezolid, Radezolid, Contezolid, Posizolid, Tedizolid, Delpazolid and TBI-223, are discussed. As they are protein synthesis inhibitors active against a wide spectrum of multidrug-resistant Gram-positive bacteria, their biological activity is carefully analyzed, together with the drug delivery systems recently developed to overcome the poor oxazolidinone water solubility. Finally, the most employed analytical techniques for oxazolidinone determination in different matrices, such as biological fluids, tissues, drugs and natural waters, are reviewed. Most are based on HPLC (High Performance Liquid Chromatography) coupled with UV-Vis or mass spectrometer detectors, but, to a lesser extent are also based on spectrofluorimetry or voltammetry. [ABSTRACT FROM AUTHOR]

Abstract: A number of benzoxazinyl-oxazolidinones bearing 3-trizolylmethyl or 3-carboxamide side chain were designed and synthesized with the aim to develop antibacterial agents with improved properties. In vitro antibacterial activities of these novel compounds were evaluated against a panel of resistant and susceptible Gram-positive bacteria. Most analogues bearing 3-trizolylmethyl showed good to moderate antibacterial activities. Compound 12a exhibited a fourfold increase in activity compared with linezolid against all the tested strains, which was identified to be a promising antibacterial agent for further evaluation. [Copyright &y& Elsevier]

Oxazolidinones (Vb), (VII), and (IX) show 2- to 3-fold greater antibacterial activities against Gram-positive, Gram-negative and linezolid-resistent pathogens than linezolid in a systemic mouse infection model. [ABSTRACT FROM AUTHOR]