- 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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- Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives
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Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5′-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity.
- Phillips, Oludotun A.,D'Silva, Roselyn,Bahta, Teklu O.,Sharaf, Leyla H.,Udo, Edet E.,Benov, Ludmil,Eric Walters
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p. 120 - 131
(2015/11/24)
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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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- NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.
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- PROCESS FOR THE PREPARATION OF CRYSTALLINE LINEZOLID
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The present invention discloses a stable crystalline Form-I of linesolid process for preparation thereof.
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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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- NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4- morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.
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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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- 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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- Process for the preparation of an oxazolidinone antibacterial agent and intermediates thereof
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Comprising a preparation process of linezolid from a compound of formula (IV) where R1 is selected from a (C4-C10)-alkyl radical which is attached to the N atom by a tertiary C atom, and a straight or branched (C3-C10)-alkenyl radical attached to the N atom such that the C=C double bond is separated from the N atom by a methylene group. Compound (IV) is submitted either first to an acetylation reaction and then to a dealkylation reaction or, alternatively, first to a dealkylation reaction and then to an acetylation reaction to yield linezolid. It also comprises new intermediate compounds useful in such a preparation process, which are obtained with high yields and high chemical and optical purity, and which are processed easily to linezolid.
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Page/Page column 8
(2010/04/24)
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- Design and synthesis of novel 5-acetylthiomethyl oxazolidinone analogs
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The oxazolidinone class of antimicrobial agents represents a promising advance in the fight against resistant Gram-positive bacterial infections. To improve antibacterial activity and expand the spectrum of activity including Gram-negative bacteria, a series of novel 5-acetylthiomethyl oxazolidinone analogs were designed and synthesized based on the structure-activity relationship studies. The structures of the target compounds and main intermediates were confirmed by 1H NMR, 13C NMR, infrared (IR), mass spectra (MS), and elemental analysis.
- Chen, Lei,Wang, Jian-Wei,Hai, Li,Wang, Guang-Ming,Wu, Yong
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experimental part
p. 789 - 798
(2010/05/18)
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- A PROCESS FOR THE PREPARATION OF (5S)-(N)-[[3-[3-FLUORO-4-(4-MORPHOLINYL) PHENYL]-2-OXO-5-OXAZOLIDINYL] METHYL] ACETAMIDE
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The present invention is directed to a novel, industrially viable, cost effective process for manufacturing (5S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide going through a novel intermediate of Formula XXI and XXII.
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Page/Page column 15
(2010/08/08)
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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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- 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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- 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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