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Huiling Jiang, Kai Lang, Hongjian Lu, Lukasz Wojtas, X Peter Zhang
Cobalt(II)-based metalloradical catalysis has been successfully applied to radical bicyclization of allyl azidoformates to construct aziridine/oxazolidinone-fused bicyclic structures. The Co(II) complex of D2-symmetric chiral amidoporphyrin 3,5-Di(t)Bu-QingPhyrin has been identified as an effective metalloradical catalyst for the intramolecular radical aziridination of this type of carbonyl azides, allowing for high-yielding formation of synthetically useful chiral [3.1.0]-bicyclic aziridines with high diastereoselectivity and enantioselectivity...
June 26, 2017: Journal of the American Chemical Society
Maria Digiacomo, Stefania Sartini, Giulia Nesi, Simona Sestito, Vito Coviello, Concettina La Motta, Simona Rapposelli
BACKGROUND: Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. OBJECTIVES: In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro-morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors...
2017: Open Medicinal Chemistry Journal
Farzad Zamani, Stephen G Pyne, Christopher J T Hyland
The simultaneous control of diastereoselectivity and regioselectivity in Zn-catalyzed allenylation reactions of N-protected L-α-amino aldehydes is reported. A reversal in diastereoselectivity could be realized by variation of the ɑ-amino aldehyde protecting groups. A range of 1-allenyl-2-amino alcohols were obtained with excellent regioselectivity and converted to oxazolidinones and dihydrofurans. Many of which could be isolated as single diastereoisomers and without significant erosion of ee, making this a practical catalytic synthesis of highly functionalized heterocycles...
May 30, 2017: Journal of Organic Chemistry
Grant A Edwards, Nataliia V Shymanska, Joshua G Pierce
Investigation into the biological function of 5-benzylidene-4-oxazolidinones revealed dose-dependent inhibition of biofilm formation in Methicillin-resistant S. aureus (MRSA). This structurally unusual class of small molecules inhibit up to 89% of biofilm formation with IC50 values as low as 0.78 μM, and disperse pre-formed biofilms with IC50 values as low as 4.7 μM. Together, these results suggest that 4-oxazolidinones represent new chemotypes to enable the study of bacterial biofilms with small molecule chemical probes...
May 24, 2017: Chemical Communications: Chem Comm
Sean M Kelly, Chong Han, Laura Tung, Francis Gosselin
We describe the highly selective copper-catalyzed Ullmann-type coupling of bromoiodoarenes with oxazolidinones. 3,4,7,8-Tetramethyl-1,10-phenanthroline (Me4Phen) was identified as an optimal ligand promoting the desired C-N bond formation, while minimizing the competitive bromo-iodo exchange pathway that leads to formation of iodo-substituted and bis-coupled side products. The developed method is highly selective with a >98:2 ratio of the bromo- vs iodo-substituted compounds obtained in the isolated products...
May 22, 2017: Organic Letters
Haiyue Long, Xiaoling Li, Zitai Sang, Lan Mei, Tao Yang, Zicheng Li, Liangxue Zhou, Yu Zheng, Gu He, Gang Guo, Zhenling Wang, Yong Deng, Youfu Luo
Antibiotic-resistance by bacteria is a growing global concern within the healthcare field, and it has provided an impetus for continued antimicrobial development. Pyrinezolid (PZ), a novel oxazolidinone compound, can effectively inhibit most gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Though PZ is a promising antimicrobial candidate, the druggability of PZ is limited by its poor water solubility. Therefore, the amphipathic mPEG-PLLA copolymer was used to prepare the pyrinezolid micelles (PZ-M)...
May 8, 2017: Colloids and Surfaces. B, Biointerfaces
Hongyi Zhao, Yu Lu, Li Sheng, Zishuo Yuan, Bin Wang, Weiping Wang, Yan Li, Chen Ma, Xiaoliang Wang, Dongfeng Zhang, Haihong Huang
A novel series of fluorine-containing benzoxazinyl-oxazolidinones were designed and synthesized as antidrug-resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound 21 exhibited not only outstanding in vitro activity with a MIC value of 0.25-0.50 μg/mL against drug-susceptible H37Rv strain and two clinically isolated drug-resistant Mycobacterium tuberculosis strains, but also acceptable in vitro ADME/T properties. Moreover, this compound displayed excellent mouse pharmacokinetic profiles with an oral bioavailability of 102% and a longer elimination half-life of 4...
May 11, 2017: ACS Medicinal Chemistry Letters
Júlia Furtado Campos, Michelly Cristiny Pereira, Wanessa Layssa Batista de Sena, Caio Gomes de Barros Martins, Jamerson Ferreira de Oliveira, Cezar Augusto da Cruz Amorim, Moacyr Jesus Barreto de Melo Rêgo, Marina Galdino da Rocha Pitta, Maria do Carmo Alves de Lima, Maira Galdino da Rocha Pitta, Ivan da Rocha Pitta
BACKGROUND: Oxazolidinones derivatives exhibit different biological properties, including anticancer activity. This work aimed to investigate the anticancer potential of five novel 2-Thioxo-oxazolidin-4-one derivatives. METHODS: Cytotoxicity assays were performed in human peripheral blood mononuclear cells (PBMCs) from healthy individuals and seven tumor cell lines. Apoptosis detection and cell cycle were evaluated by flow cytometry and the expression of genes involved in cell death processes by Real-Time PCR...
March 18, 2017: Pharmacological Reports: PR
Narasimhulu Manchala, Hanson Yeu Leuk Law, Daniel Jarrah Kerr, Rohan Volpe, Romain J Lepage, Jonathan M White, Elizabeth H Krenske, Bernard L Flynn
Achieving ready enantioselective access to multi-stereocenter containing cyclopentyl rings is an area of great significance to organic synthesis. In this work we describe a general protocol for accessing multi-stereocenter containing cyclopentanoids from simple N-alkynyloxazolidinones (Ox-ynamides). This protocol involves conversion of Ox-ynamides into Ox-activated divinyl and aryl vinyl ketones that undergo facile Nazarov cyclization with excellent chemo-, regio- and stereocontrol. The Ox auxiliary directs all aspects of reactivity and selectivity, both the electrocyclization and in the subsequent transformations of the resulting oxyallyl intermediate...
May 16, 2017: Journal of Organic Chemistry
Matthew J Belousoff, Zohar Eyal, Mazdak Radjainia, Tofayel Ahmed, Rebecca S Bamert, Donna Matzov, Anat Bashan, Ella Zimmerman, Satabdi Mishra, David Cameron, Hans Elmlund, Anton Y Peleg, Shashi Bhushan, Trevor Lithgow, Ada Yonath
An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site...
May 9, 2017: MBio
Michael A Pfaller, Rodrigo E Mendes, Jennifer M Streit, Patricia A Hogan, Robert K Flamm
This study describes linezolid susceptibility testing results for 6,741 gram-positive pathogens from 60 U.S. sites collected during 2015 for the LEADER Program. In addition, the study summarizes linezolid in vitro activity, resistance mechanisms, and molecular typing obtained for 2011 to 2015. During 2015, linezolid showed potent activity when tested against Staphylococcus aureus, inhibiting >99.9% of 3,031 isolates at ≤2 mg/liter. Similarly, linezolid showed coverage against 99.2% of coagulase-negative staphylococci, 99...
May 8, 2017: Antimicrobial Agents and Chemotherapy
Xue-Dong Li, Qing-Wen Song, Xian-Dong Lang, Yao Chang, Liang-Nian He
Chemical valorization of CO2 to access various value-added compounds has been a long-term and challenging objective from the viewpoint of sustainable chemistry. Herein, a one-pot three-component reaction of terminal propargyl alcohols, CO2 , and 2-aminoethanols was developed for the synthesis of 2-oxazolidinones and an equal amount of α-hydroxyl ketones promoted by Ag2 O/TMG (1,1,3,3-tetramethylguanidine) with a TON (turnover number) of up to 1260. By addition of terminal propargyl alcohol, the thermodynamic disadvantage of the conventional 2-aminoethanol/CO2 coupling was ameliorated...
May 2, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
Katarzyna Michalska, Ewa Gruba, Mikołaj Mizera, Kornelia Lewandowska, Elżbieta Bednarek, Wojciech Bocian, Judyta Cielecka-Piontek
In the presented study, N-{[(5S)-3-(2-fluoro-4'-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (radezolid) was synthesized and characterized using FT-IR, Raman, ECD and NMR. The aim of this work was to assess the possibility of applying classical spectral methods such as FT-IR, Raman, ECD and NMR spectroscopy for studies on the identification and optical purity of radezolid. The experimental interpretation of FT-IR and Raman spectra of radezolid was conducted in combination with theoretical studies...
April 20, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Zackaria Nairoukh, Gunda G K S Narayana Kumar, Yury Minko, Ilan Marek
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.
January 1, 2017: Chemical Science
Johanna Marcela Vanegas Múnera, Ana María Ocampo Ríos, Daniela Montoya Urrego, Judy Natalia Jiménez Quiceno
INTRODUCTION: Treatment of multidrug-resistant Gram-positive infections caused by Staphylococcus aureus remains as a clinical challenge due to emergence of new resistance mechanisms. Tedizolid is a next-generation oxazolidinone, recently approved for skin and soft tissues infections. We conducted a study to determine in vitro susceptibility to vancomycin, daptomycin, linezolid, and tedizolid in MRSA clinical isolates from adult patients with skin and soft tissue infections. MATERIAL AND METHODS: Methicillin-resistant S...
April 19, 2017: Brazilian Journal of Infectious Diseases
Sheng Si, Michael J Durkin, Maureen M Mercier, Melanie L Yarbrough, Stephen Y Liang
Few antibiotic options exist for the management of infections due to vancomycin-resistant enterococci (VRE). We describe a case involving the safe and successful use of tedizolid, a new oxazolidinone, to treat VRE prosthetic joint infection.
March 2017: Infectious Diseases in Clinical Practice: IDCP
Arun K Ghosh, Margherita Brindisi, Yu-Chen Yen, Emilio L Cárdenas, Jean-Rene Ella-Menye, Nagaswamy Kumaragurubaran, Xiangping Huang, Jordan Tang, Andrew D Mesecar
We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki=2nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
Hélène Lebel, Laura Mamani Laparra, Maroua Khalifa, Carl Trudel, Clément Audubert, Mathieu Szponarski, Cédric Dicaire Leduc, Emna Azek, Matthias Ernzerhof
N-Mesyloxycarbamates undergo intramolecular C-H amination reactions to afford oxazolidinones in good to excellent yields in the presence of rhodium(ii) carboxylate catalysts. The reaction is performed under green conditions and potassium carbonate is used, forming biodegradable potassium mesylate as a reaction by-product. This method enables the production of electron-rich, electron-deficient, aromatic and heteroaromatic oxazolidinones in good to excellent yields. Conformationally restricted cyclic secondary N-mesyloxycarbamates furnish cis-oxazolidinones in high yields and selectivity; DFT calculations are provided to account for the observed selectivity...
May 16, 2017: Organic & Biomolecular Chemistry
Fabio Cafini, Nguyen Thi Le Thuy, Federico Román, José Prieto, Sarah Dubrac, Tarek Msadek, Kazuya Morikawa
One important feature of the major opportunistic human pathogen Staphylococcus aureus is its extraordinary ability to rapidly acquire resistance to antibiotics. Genomic studies reveal that S. aureus carries many virulence and resistance genes located in mobile genetic elements, suggesting that horizontal gene transfer (HGT) plays a critical role in S. aureus evolution. However, a full and detailed description of the methodology used to study HGT in S. aureus is still lacking, especially regarding natural transformation, which has been recently reported in this bacterium...
March 10, 2017: Journal of Visualized Experiments: JoVE
Barbara A Brown-Elliott, Richard J Wallace
Tedizolid is a new oxazolidinone with improved in vitro and intracellular potency against Mycobacterium tuberculosis, including multidrug-resistant strains, and some species of nontuberculous mycobacteria (NTM) compared with that of linezolid. Using the current Clinical and Laboratory Standards Institute (CLSI)-recommended method of broth microdilution, susceptibility testing of 170 isolates of rapidly growing mycobacteria showed equivalent or lower (1- to 8-fold) MIC50 and/or MIC90 values for tedizolid compared with that for linezolid...
June 2017: Journal of Clinical Microbiology
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