- 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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p. 5310 - 5321
(2017/11/13)
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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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- 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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- A PROCESS FOR THE PREPARATION OF TEDIZOLID PHOSPHATE
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The present invention provides a process for the preparation of tedizolid phosphate.
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- Method for preparing tedizolid phosphate
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The invention relates to the technical field of preparation of tedizolid phosphate, and especially relates to a preparation method of tedizolid phosphate. According to the invention, 3-fluoroaniline is taken as a raw material, and is subjected to a nucleophilic substitution reaction with (R)-(-)-glycidyl butyrate, then a cyclization reaction and hydrolysis are carried out, protective group is removed to obtain a compound (VI); the compound (VI) is subjected to an iodination reaction and the nucleophilic substitution reaction to obtain a compound (VIII); the compound (VIII) and 2-(1-methyl-tetrazolium-5-group)-5-bromopyridine (IX) are reacted, and then a target product (I) is obtained with phosphoric acid. The method has the advantages of short route, mild reaction condition, and easy post-treatment, and is more suitable for industrial production requirement.
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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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- 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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- 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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p. 1027 - 1039
(2011/04/17)
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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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- 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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- 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 24
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ARYL SUBSTITUTED OXAZOLIDINONES AS INTERMEDIATES FOR ANTIBACTERIAL AGENTS
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A compound of the formula (VIII) wherein each X is independently H or F; and R is selected from hydrogen, halogen, cyano, methyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl and -Si[(1-4C)alkyl]3; and processes for preparing a co
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Page/Page column 22-23
(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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- Substituted aryl- and heteroaryl-phenyloxazolidinones
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The present invention discloses novel substituted aryl- and heteroarylphenyloxazolidinones which are useful as anti-bacterial agents. More specifically, the substituted aryl- and heteroarylphenyloxazolidinones of the invention are characterized by oxazoli
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- Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents. 2. Modification of the phenyl ring - The potentiating effect of fluorine substitution on in vivo activity
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Various electron-withdrawing groups were incorporated into the meta position of tropone-substituted 3-phenyl-2-oxazolidinones and their influence on antibacterial activity examined. Consideration of in vitro and in vivo test results indicated that one or two fluorine atoms flanking the para tropone appendage is the optimum arrangement for these compounds. Synthetic routes to enantiomerically enriched analogues are reported. Copyright
- Barbachyn, Michael R.,Toops, Dana S.,Grega, Kevin C.,Hendges, Susan K.,Ford, Charles W.,Zurenko, Gary E.,Hamel, Judith C.,Schaadt, Ronda D.,Stapert, Douglas,Yagi, Betty H.,Buysse, Jerry M.,Demyan, William F.,Kilburn, James O.,Glickman, Suzanne E.
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p. 1009 - 1014
(2007/10/03)
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