- Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity
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gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.
- Sun, Alexander W.,Bulterys, Philip L.,Bartberger, Michael D.,Jorth, Peter A.,O'Boyle, Brendan M.,Virgil, Scott C.,Miller, Jeff F.,Stoltz, Brian M.
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supporting information
p. 2686 - 2689
(2019/08/07)
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- Compound design guidelines for evading the efflux and permeation barriers of Escherichia coli with the oxazolidinone class of antibacterials: Test case for a general approach to improving whole cell Gram-negative activity
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Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (7.4 1), and iii) zwitterionic character at pH 7.4. Indeed, we observed that only analogs residing within these limits were able to overcome these barriers. Herein we report the results from a parallel effort where we explored structural changes throughout all three rings in the scaffold for the same purpose. Compounds were tested against a diagnostic MIC panel of Escherichia coli and Staphylococcus aureus strains to determine the impact of combining structural modifications in overcoming the OM barriers and in bridging the potency gap between the species. The results demonstrated that distributing the charge-carrying moieties across two rings was also beneficial for avoidance of the outer membrane barriers. Importantly, analysis of the structure-permeation relationship (SPR) obtained from this and the prior study indicated that in addition to MW, polarity, and zwitterionic character, having ≤4 rotatable bonds is also associated with evasion of the OM barriers. These combined results provide the medicinal chemist with a framework and strategy for overcoming the OM barriers in GNB in antibacterial drug discovery efforts.
- Spaulding, Andrew,Takrouri, Khuloud,Mahalingam, Pornachandran,Cleary, Dillon C.,Cooper, Harold D.,Zucchi, Paola,Tear, Westley,Koleva, Bilyana,Beuning, Penny J.,Hirsch, Elizabeth B.,Aggen, James B.
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supporting information
p. 5310 - 5321
(2017/11/13)
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- Preparation method of biaryl oxazolidone intermediate
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The invention relates to a preparation method of a biaryl oxazolidone intermediate (5S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxooxazolidine-5-ol]methyl]acetamine (I). According to the method, the intermediate is prepared with m-fluoroaniline as an initial raw material through amino protection, iodination and cyclization sequentially. Compared with a reported preparation method of the biaryl oxazolidone intermediate, the method adopts a short route, increases the yield, greatly reduces the cost and is more suitable for industrial production.
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Paragraph 0045-0047
(2017/07/11)
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- A Simple, efficient, Catalyst-Free and Solvent-Less Microwave-Assisted process for N-Cbz Protection of Several amines
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A simple, green and chemo-selective method for the N-benzyloxycarbonylation of amines, β-amino alcohols, α-amino esters and sulfonamides has been developed under microwave irradiation. Good to excellent yields of the N-benzyloxy-carbamates compounds were obtained in short times without any side products.
- Aouf, Zineb,Mansouri, Rachida,Lakrout, Salah,Berredjem, Malika,Aouf, Nour-Eddine
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p. 151 - 156
(2017/08/02)
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- Application of spectroscopic methods (FT-IR, Raman, ECD and NMR) in studies of identification and optical purity of radezolid
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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 t
- Michalska, Katarzyna,Gruba, Ewa,Mizera, Miko?aj,Lewandowska, Kornelia,Bednarek, El?bieta,Bocian, Wojciech,Cielecka-Piontek, Judyta
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supporting information
p. 116 - 122
(2017/04/28)
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- TOPICAL FORMULATIONS OF BIARYL HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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The present invention relates to topical formulations of biaryl heterocyclic compounds and methods of use thereof for treating acne and other skin infections caused or mediated by Streptococcus pyogenes, Streptococcus agalactiae, Haemophilus influenza, Trichomonas vaginalis, Klebsiella sp., Enterobacter sp., Proteus sp., Propionibacterium acnes, Gardnerella vaginalis, or Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus (MRSA)) in a patient in need thereof. In certain embodiments, the acne or other skin infection is caused or mediated by Propionibacterium acnes, Gardnerella vaginalis, or Staphylococcus aureus.
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Paragraph 0194
(2017/12/15)
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- A oxazolidinone compounds of preparation method (by machine translation)
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The invention provides a oxazolidinone compounds of the preparation method. Specifically provides the type 1 compound preparation method. The formula 1 compound preparation method comprises, formula 2 N - methyl - D - grape amine compound in the presence of a catalytic reduction, direct formula 1 compound. The present invention provides a preparation has simplified the reaction step, shorten the reaction route, can make the final yield of the product is higher, and, better purity. (by machine translation)
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Paragraph 0044
(2017/05/12)
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- METHOD FOR TREATING, PREVENTING, OR REDUCING THE RISK OF SKIN INFECTION
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The present invention relates to methods for treating acne and other skin infections caused or mediated by Propionibacterium acnes, Gardnerella vaginalis, or Staphylococcus aureus in a patient with a safe and effective amount of a topically applied oxazolidinone antibiotic compound.
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Paragraph 0210; 0211
(2016/06/06)
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- An improved efficient synthesis of the antibacterial agent torezolid
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An improved and efficient method for the preparation of torezolid based on Suzuki cross-coupling reaction as the key step was developed on a gram scale in five steps. The total yield was 44% and the optical purity of torezolid by the improved method was above 99%.
- Li, Gang,Yuan, Bao-Kun,Tang, Wu,Zhao, Hong-Yi,Lin, Zi-Yun,Huang, Hai-Hong
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p. 143 - 146
(2015/02/19)
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- Synthesis and in vitro activity of novel 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinone antibacterial agents. Part II
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The synthesis and antibacterial activity of 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinones is reported. Compound 3e with a 2,4-disubstituted thiophene ring was found to be a potent inhibitor of Gram-positive pathogens and was 4-16-fold more potent than Linezolid.
- Khera, Manoj Kumar,Cliffe, Ian A.,Prakash, Om
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p. 5266 - 5269
(2011/10/02)
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- Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent
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A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure-activity relationship (SAR) was investigated based on in vitro and in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0 μg/mL, and against Haemophilus influenzae (Hi) from 2.0 to 8.0 μg/mL. Compared to linezolid, only four compounds (11, 12, 21 and 29) showed higher in vitro antibacterial activities and better in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound 11 (DA-7157), which exerted a potency that was enhanced by 2-8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound 42 exhibited excellent aqueous solubility (>50 mg/mL in DW) and good pharmacokinetic profiles, along with better in vivo efficacy than linezolid. This compound 42 is currently undergoing clinical trials with the brand name Torezolid.
- Im, Weon Bin,Choi, Sun Ho,Park, Ju-Young,Choi, Sung Hak,Finn, John,Yoon, Sung-Hwa
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experimental part
p. 1027 - 1039
(2011/04/17)
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- Process for the synthesis of triazoles
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The present invention relates to processes for the preparation of triazoles. These compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.
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Page/Page column 36
(2010/09/18)
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- Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones
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A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand-enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar antiviral potency against patient-derived viruses from HIV-1 clades A, B, and C, and most retained potency against drug-resistant viruses. Further optimization of these compounds using structure-based design may lead to the development of novel protease inhibitors with improved activity against drug-resistant strains of HIV-1.
- Ali, Akbar,Reddy, G. S. Kiran Kumar,Nalam, Madhavi N. L.,Anjum, Saima Ghafoor,Cao, Hong,Schiffer, Celia A.,Rana, Tariq M.
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scheme or table
p. 7699 - 7708
(2010/12/30)
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- Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands
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Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2′ phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with Ki values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2′ phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1′ with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogen-bond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (Ki = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar Ki, which is highly comparable with the best FDA-approved protease inhibitors.
- Ali, Akbar,Reddy, G. S. Kiran Kumar,Cao, Hong,Anjum, Saima Ghafoor,Nalam, Madhavi N. L.,Schiffer, Celia A.,Rana, Tariq M.
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p. 7342 - 7356
(2007/10/03)
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- NOVEL OXAZOLIDINONE DERIVATIVES
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The present invention relates to novel derivatives of oxazolidinone, a method thereof and pharmaceutical compositions comprising the derivatives for use in an antibiotic. The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria and lower toxicity. The prodrugs, prepared by reacting the compound having hydroxyl group with amino acid or phosphate, have an excellent efficiency on solubility thereof against water. Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium. Accordingly, the compositions comprising the oxazolidinone are used in an antibiotic.
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Page/Page column 23; 24
(2008/06/13)
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- Novel oxazolidinone derivatives and a process for the preparation thereof
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The present invention relates to novel oxazolidinone derivatives, their pharmaceutically acceptable salts and a process for the preparation thereof. More particularly, the present invention relates to oxazolidinone derivatives having pyridine or pyrimidine moeity substituted by heterocycle and heteroaromaticcycle at 4-position of phenyl ring. The compounds of the present invention have wide antibacterial spectrum, superior antibacterial activity and low toxicity, such that the compound of this invention can be used as an antibacterial agent.
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