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
- PMID:8576909
- DOI: 10.1021/jm9509556
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
Abstract
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.
Similar articles
- Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity.Barbachyn MR, Hutchinson DK, Brickner SJ, Cynamon MH, Kilburn JO, Klemens SP, Glickman SE, Grega KC, Hendges SK, Toops DS, Ford CW, Zurenko GE.Barbachyn MR, et al.J Med Chem. 1996 Feb 2;39(3):680-5. doi: 10.1021/jm950956y.J Med Chem. 1996.PMID:8576910
- Synthesis and antibacterial activity of novel (un)substituted benzotriazolyl oxazolidinone derivatives.Dixit PP, Nair PS, Patil VJ, Jain S, Arora SK, Sinha N.Dixit PP, et al.Bioorg Med Chem Lett. 2005 Jun 15;15(12):3002-5. doi: 10.1016/j.bmcl.2005.04.045.Bioorg Med Chem Lett. 2005.PMID:15908210
- Synthesis and antibacterial activity of dihydro-1,2-oxazine and 2-pyrazoline oxazolidinones: novel analogs of linezolid.D'Andrea S, Zheng ZB, Denbleyker K, Fung-Tomc JC, Yang H, Clark J, Taylor D, Bronson J.D'Andrea S, et al.Bioorg Med Chem Lett. 2005 Jun 2;15(11):2834-9. doi: 10.1016/j.bmcl.2005.03.099.Bioorg Med Chem Lett. 2005.PMID:15911264
- Recent developments in the discovery of novel oxazolidinone antibacterials.Gravestock MB.Gravestock MB.Curr Opin Drug Discov Devel. 2005 Jul;8(4):469-77.Curr Opin Drug Discov Devel. 2005.PMID:16022183Review.
- Oxazolidinones--a new class of broad-spectrum chemotherapeutics.Sztanke K, Pasternak K, Sztanke M.Sztanke K, et al.Ann Univ Mariae Curie Sklodowska Med. 2004;59(2):335-41.Ann Univ Mariae Curie Sklodowska Med. 2004.PMID:16146103Review.
Cited by
- Telavancin: a novel semisynthetic lipoglycopeptide agent to counter the challenge of resistant Gram-positive pathogens.Das B, Sarkar C, Das D, Gupta A, Kalra A, Sahni S.Das B, et al.Ther Adv Infect Dis. 2017 Mar;4(2):49-73. doi: 10.1177/2049936117690501. Epub 2017 Mar 8.Ther Adv Infect Dis. 2017.PMID:28634536Free PMC article.Review.
- Accelerated Chemical Reaction Optimization Using Multi-Task Learning.Taylor CJ, Felton KC, Wigh D, Jeraal MI, Grainger R, Chessari G, Johnson CN, Lapkin AA.Taylor CJ, et al.ACS Cent Sci. 2023 Apr 13;9(5):957-968. doi: 10.1021/acscentsci.3c00050. eCollection 2023 May 24.ACS Cent Sci. 2023.PMID:37252348Free PMC article.
- Linezolid dependence in Staphylococcus epidermidis bloodstream isolates.Pournaras S, Ntokou E, Zarkotou O, Ranellou K, Themeli-Digalaki K, Stathopoulos C, Tsakris A.Pournaras S, et al.Emerg Infect Dis. 2013 Jan;19(1):129-32. doi: 10.3201/eid1901.111527.Emerg Infect Dis. 2013.PMID:23260390Free PMC article.
- Liquid chromatographic estimation of (S) - glycidyl butyrate in (R) - glycidyl butyrate.Khan MA, Sinha S, Khandekar N, Parashar V.Khan MA, et al.J Nat Sci Biol Med. 2011 Jul;2(2):180-4. doi: 10.4103/0976-9668.92331.J Nat Sci Biol Med. 2011.PMID:22346232Free PMC article.
- Syntheses and antibacterial activity studies of new oxazolidinones from nitroso Diels-Alder chemistry.Yan S, Miller MJ, Wencewicz TA, Möllmann U.Yan S, et al.Bioorg Med Chem Lett. 2010 Feb 1;20(3):1302-5. doi: 10.1016/j.bmcl.2009.10.018. Epub 2009 Oct 8.Bioorg Med Chem Lett. 2010.PMID:20031407Free PMC article.
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources
Other Literature Sources