- Synthesis of covalent bonding MWCNT-oligoethylene linezolid conjugates and their antibacterial activity against bacterial strains
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Nowadays, infectious diseases caused by drug-resistant bacteria have become especially important. Linezolid is an antibacterial drug active against clinically important Gram positive strains; however, resistance showed by these bacteria has been reported. Nanotechnology has improved a broad area of science, such as medicine, developing new drug delivery and transport systems. In this work, several covalently bounded conjugated nanomaterials were synthesized from multiwalled carbon nanotubes (MWCNTs), a different length oligoethylene chain (Sn), and two linezolid precursors (4and7), and they were evaluated in antibacterial assays. Interestingly, due to the intrinsic antibacterial activity of the amino-oligoethylene linezolid analogues, these conjugated nanomaterials showed significant antibacterial activity against various tested bacterial strains in a radial diffusion assay and microdilution method, including Gram negative strains asEscherichia coli(11 mm, 6.25 μg mL?1) andSalmonella typhi(14 mm, ≤0.78 μg mL?1), which are not inhibited by linezolid. The results show a significant effect of the oligoethylene chain length over the antibacterial activity. Molecular docking of amino-oligoethylene linezolid analogs shows a more favorable interaction of theS2-7analog in the PTC ofE. coli.
- Alatorre-Barajas, José A.,Alcántar-Zavala, Eleazar,Alonso-Nú?ez, Gabriel,Cabrera, Alberto,Estrada-Zavala, Edgar,Gil-Rivas, M. Graciela,Gochi-Ponce, Y.,Medina-Franco, J. L.,Montes-ávila, Julio,Ochoa-Terán, Adrián,Reynoso-Soto, Edgar A.,Rivera-Lugo, Yazmin Yorely,Trujillo-Navarrete, Balter
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p. 28912 - 28924
(2021/09/22)
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- Modular click chemistry libraries for functional screens using a diazotizing reagent
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Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties1. Copper(i)-catalysed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur(vi) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions2–4, providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups5. The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide6–11 (FSO2N3), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science.
- Meng, Genyi,Guo, Taijie,Ma, Tiancheng,Zhang, Jiong,Shen, Yucheng,Sharpless, Karl Barry,Dong, Jiajia
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- PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF LINEZOLID AND ITS COMPOSITIONS
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The present invention relates to a process for the preparation of crystalline form I of linezolid, comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at elevated temperature. The present invention also relates to the use of crystalline form I of linezolid prepared by the method of the present invention for preparing pharmaceutical compositions.
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- PROCESS FOR PREPARATION OF OXAZOLIDINONE DERIVATIVES
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A process for preparation of oxazolidinone derivatives such as Linezolid and Rivaroxaban using (S)-Epichlorohydrin.
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Page/Page column 30; 31
(2014/11/11)
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- Novel promising linezolid analogues: Rational design, synthesis and biological evaluation
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A new series of 5-substituted oxazolidinones derived from linezolid, having urea and thiourea moieties at the C-5 side chain of the oxazolidinone ring, were prepared and their in vitro antibacterial activity was evaluated. The compound 10f demonstrated high antimicrobial activity, comparable to that of linezolid against Staphylococcus aureus.
- De Rosa, Margherita,Zanfardino, Anna,Notomista, Eugenio,Wichelhaus, Thomas A.,Saturnino, Carmela,Varcamonti, Mario,Soriente, Annunziata
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p. 779 - 785
(2013/10/22)
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- A facile solvent-free synthesis of chiral oxazolidinone derivatives catalyzed by MgI2 etherate: An approach to enantiopure synthesis of linezolid
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A highly efficient and stereoselective cycloaddition of aryl isocyanates with chiral oxiranes catalyzed by MgI2 etherate under solvent-free conditions was developed to prepare the chiral oxazolidinone derivatives. This methodology has been applied into the practical synthesis of antibacterial drug linezolid.
- Zhang, Xingxian,Zhao, Chengfeng,Gu, Yue
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p. 1143 - 1146,4
(2020/09/16)
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- AMINATION OF ARYL ALCOHOL DERIVATIVES
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Embodiments of the invention provide methods and materials for chemical cross-coupling reactions that utilize aryl alcohol derivatives as cross-coupling partners. Embodiments of the invention include methods for the amination of aryl sulfamates and carbamates, which are attractive cross-coupling partners, particularly for use in multistep synthesis. Illustrative embodiments include versatile means to use simple derivatives of phenol as precursors to polysubstituted aryl amines, as exemplified by a concise synthesis of the antibacterial drug linezolid.
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- An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: A short and efficient synthesis of Linezolid
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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. ARKAT-USA, Inc.
- Tammana, Rajesh,Vemula, Kiran Kumar,Guruvindapalli, Ramadasu,Yanamandr, Ramesh,Gutta, Madhusudhan
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experimental part
p. 45 - 56
(2012/03/11)
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- PROCESSES FOR THE PREPARATION OF LINEZOLID
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Disclosed herein a process for preparing linezolid, wherein the resultant linezolide is devoid of impurities and involve easy and economical process. The present invention further relates to preparation of linezolid by employing an azide intermediate and process for said intermediate.
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- Nickel-catalyzed amination of aryl sulfamates
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Broad in scope: The first amination of aryl sulfamates, which are attractive cross-coupling partners, particularly for multistep syntheses, was achieved by using a nickel catalyst. The method provides a versatile means to use simple derivatives of phenol as precursors to polysubstituted aryl amines, as exemplified by a concise synthesis of the antibacterial drug linezolid (see scheme).
- Ramgren, Stephen D.,Silberstein, Amanda L.,Yang, Yang,Garg, Neil K.
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p. 2171 - 2173
(2011/04/25)
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- PROCESS FOR THE PREPARATION OF LINEZOLID
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The present invention provides an improved process for the preparation of Linezolid of formula (D. The present invention relates to preparation of intermediate (R)-N-[[3-[3-fluoro-4-morpholinyl] phenyl |-2-oxo-5-oxazolidinyl] methanol of formula (II), Linezolid amine of formula (Ia) and their use in the preparation of Linezolid. The present invention further provides process for the preparation of Form I of Linezolid of formula (I).
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- A new practical synthesis of linezolid: An antibacterial drug
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A novel and practical asymmetric synthesis of (S)-N-[[3-(3-fluoro-4- morpholinyl phenyl)-2-oxo-5-oxazo- lidinyl]methyl]acetamide has been developed by a new approach without recourse to chromatography and it is employed for the synthesis of Linezolid. This involves the reaction of (R)-epichlorohydrin with N-arylcarbamates and subsequent regioselective epoxide ring opening of resulted intermediate by sodium azide.
- Reddy, Ganta Madhusudhan,Ramulu, Akula,Reddy, Padi Pratap
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experimental part
p. 45 - 49
(2010/08/13)
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- An efficient and practical synthesis of antibacterial linezolid
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A convergent and efficient synthesis of linezolid was developed using the cycloaddition of commercially available (R)-epichlorohydrin with morpholine substituted phenylisocyanate catalysed by MgI2 or MgBr2 etherate as the key step in the 50% overall yield.
- Zhang, Xingxian,Chen, Wei,Li, Cheng,Wu, Xiang
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experimental part
p. 739 - 740
(2010/03/24)
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- PROCESS FOR PREPARATION OF (S) (N-[[3-[3-FLUORO-4-(4-MORPHOLINYL) HEN L -2-OXO-5-OXAZOLIDIN L METHYL]ACETAMIDE
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The present invention provides novel process for preparation of (S)-N-[[3-[3-Fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] -acetamide which comprises combining (R)-N-[3-[3-fluoro-4-morpholinyl phenyl]-2-oxo-5-oxazolidinyl]methylazide in suitable solvent, acetylating agent and acid in presence of a catalyst.
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Page/Page column 14
(2009/06/27)
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- Synthesis and antibacterial activity of novel 5-(4-methyl-1H-1,2,3-triazole) methyl oxazolidinones
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A series of 5-(4-methyl-1,2,3-triazole)methyl oxazolidinones were synthesized and tested for their antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates in comparison with linezolid and vancomycin. Most of the compounds demonstrated strong to moderate in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria. Antibacterial activity varied with substitutions at the phenyl C4 position with bulky alkylcarbonyl and alkoxycarbonyl substitutions on the piperazine N4 being detrimental to antibacterial activity. Whereas the presence of the 4-methyl-1,2,3-triazole moiety in the acyl-piperazine containing analogs resulted in increased protein binding, and decreased antibacterial activity particularly against Streptococcus pneumoniae strains.
- Phillips, Oludotun A.,Udo, Edet E.,Abdel-Hamid, Mohammed E.,Varghese, Reny
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scheme or table
p. 3217 - 3227
(2009/12/04)
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- Stereoselective synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones from (S)-epichlorohydrin: a key precursor for the oxazolidinone class of antibacterial agents
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A facile synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones starting from (S)-epichlorohydrin is described. The (R)-azide was utilized for the preparation of Linezolid.
- Madhusudhan,Om Reddy,Rajesh,Ramanatham,Dubey
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p. 3060 - 3062
(2008/09/20)
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- A convenient synthesis of oxazolidinone derivatives linezolid and eperezolid from (S)-glyceraldehyde acetonide
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A 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 A sieve, followed by hydrolysis and regioselective cyclization.
- Guangyu, Xu,Yi, Zhou,Chunhao, Yang,Yuyuan, Xie
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p. 316 - 319
(2008/09/19)
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- An exploratory and mechanistic study of the defluorination of an (aminofluorophenyl)oxazolidinone: SN1(Ar*) vs. S R+N1(Ar*) mechanism
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The morpholinofluorophenyloxazolidinone 1 (the antibacterial drug linezolid) is found to undergo reductive defluorination upon irradiation in water (Φ 0.33), in some of the products accompanied by the simultaneous oxidative degradation of the morpholine side chain. In the presence of chloride, iodide and pyrrole, the fluorine is substituted by these groups (with pyrrole, in position 2). The defluorination is less efficient in methanol and mainly leads to reduction (Φ 0.053). These data can be accommodated through two different mechanisms, viz. either C-F bond heterolysis to give a phenyl cation [SN1(Ar*)], or ionization to give a radical cation [S R+N1(Ar*)]. Steady-state and time resolved data have been gathered for clarifying this issue. It is found that, indeed, ionization of 1 is efficient and proceeds from the singlet, but leads to no irreversible change. On the contrary, triplet 31 (lifetime 0.5 μs in MeOH, 0.1 μs in water) fragments and gives the corresponding triplet phenyl cation. The last intermediate explains well the observed hydrogen abstraction both inter- (from the solvent, when this is reducing) and intramolecularly (from the morpholine group), as well as addition to a charged anion or to a neutral π nucleophile such as pyrrole. The rationalization is supported by the study of some related molecules. Thus, the only photochemical reaction from the non fluorinated analogue of linezolid (that ionizes just as 1) is an inefficient degradation of the morpholine chain (Φ 0.001), while a simple model such as N-(2-fluorophenyl)morpholine undergoes photosolvolysis in water and is not trapped by pyrrole.
- Fasani, Elisa,Tilocca, Fedele,Protti, Stefano,Merli, Daniele,Albini, Angelo
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experimental part
p. 4634 - 4642
(2009/03/12)
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- Short and practical enantioselective synthesis of linezolid and eperezolid via proline-catalyzed asymmetric α-aminooxylation
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An efficient enantioselective synthesis of the antibacterials, linezolid (U-100766), and eperezolid (U-100592) using d-proline-catalyzed asymmetric α-aminooxylation of aldehydes as the key step is described here. This is the first report on the enantioselective synthesis of linezolid and eperezolid using asymmetric catalysis.
- Narina, Srinivasarao V.,Sudalai, Arumugam
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p. 6799 - 6802
(2007/10/03)
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- A novel and short convergent approach for N-aryl-5-aminomethyl-2- oxazolidinone derivatives Linezolid and DUP-721
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A new convergent and short approach for oxazolidinone class of antibacterial agents, Linezolid and DUP-721, has been achieved by condensing 3-chloro-2-((phenoxycarbonyl)oxy) propyl azide with aryl amine followed by reductive acetylation. This one pot approach for N-aryl-5-azidomethyl- 2-oxazolidinone could provide access for rapid preparation of various oxazolidinone analogues.
- Madhusudhan,Om Reddy,Ramanatham,Dubey
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p. 1236 - 1238
(2007/10/03)
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- Synthesis and antibacterial activity of 5-substituted oxazolidinones
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A series of 5-substituted oxazolidinones with varying substitution at the 5-position of the oxazolidinone ring were synthesized and their in vitro antibacterial activity was evaluated. The compounds demonstrated potent to weak antibacterial activity. A novel compound (PH-027) demonstrated potent antibacterial activity, which is comparable to or better than those of linezolid and vancomycin against antibiotic-susceptible standard and clinically isolated resistant strains of gram-positive bacteria. Although the presence of the C-5-acetamidomethyl functionality at the C-5 position of the oxazolidinones has been widely claimed and reported as a structural requirement for optimal antimicrobial activity in the oxazolidinone class of compounds, our results from this work identified the C-5 triazole substitution as a new structural alternative for potent antibacterial activity in the oxazolidinone class.
- Phillips,Udo,Ali,Al-Hassawi
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- Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 2.1) Relationship between lipophilicity and antibacterial activity in 5-thiocarbonyl oxazolidinones
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5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacterial agents considering the hydrophobic parameters of the molecule. The structure-activity relationship (SAR) study revealed that the antibacterial activity on 5-thiocarbonyl oxazolidinones was significantly affected by the lipophilicity, especially the calculated log P value and the balance between 5-hydrophilic (or hydrophobic) substituent and hydrophobic (or hydrophilic) substituents on the benzene ring. Some of 5-thiocarbonyl oxazolidinones were found to have good in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
- Tokuyama,Takahashi,Tomita,Tsubouchi,Yoshida,Iwasaki,Kado,Okezaki,Nagata
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p. 353 - 360
(2007/10/03)
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- A short synthesis of oxazolidinone derivatives linezolid and eperezolid: A new class of antibacterials
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Oxazolidinone derivatives such as Linezolid and Eperazolid, which are a new class of antibacterials, have been synthesized from 1,2,5,6-dianhydro- 3,4-isopropylidine-D-mannitol in good yield.
- Lohray, Braj B.,Baskaran, Sundarababu,Rao, B. Srinivasa,Reddy, B. Yadi,Rao, I. Nageswara
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p. 4855 - 4856
(2007/10/03)
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- Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections.
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Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.
- Brickner, Steven J.,Hutchinson, Douglas K.,Barbachyn, Michael R.,Manninen, Peter R.,Ulanowicz, Debra A.,et al.
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p. 673 - 679
(2007/10/03)
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