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1.
Katarzyna Michalska Izabela Karpiuk Marek Król Stefan Tyski 《Bioorganic & medicinal chemistry》2013,21(3):577-591
The oxazolidinones are a new and potent class of antimicrobial agents with activity mainly against Gram-positive strains. The commercial success of linezolid, the only FDA-approved oxazolidinone, has prompted many pharmaceutical companies to devote resources to this area of investigation. Until now, four types of chemical modifications of linezolid and oxazolidinone-type antibacterial agents, including modification on each of the A-(oxazolidinone), B-(phenyl), and C-(morpholine) rings as well as the C-5 side chain of the A-ring substructure, have been described. Division into sections according to side chain modification or the type of ring will be used throughout this review, although the process of synthesis usually involves the simultaneous modification of several elements of the linezolid substructure; therefore, assignment into the appropriate section depends on the structure–activity relationships (SAR) studies.This review makes an attempt to summarise the work carried out in the period from 2006 until mid-2012. 相似文献
2.
Takhi M Murugan C Munikumar M Bhaskarreddy KM Singh G Sreenivas K Sitaramkumar M Selvakumar N Das J Trehan S Iqbal J 《Bioorganic & medicinal chemistry letters》2006,16(9):2391-2395
Novel oxazolidinone antibacterials containing N-hydroxyacetamidine moiety are synthesized with the diversity at C-5 terminus. These compounds have been evaluated against a panel of clinically relevant gram-positive and gram-negative pathogens. Most of the analogs in this series displayed activity superior to Linezolid and in vivo efficacies of selected oxazolidinones are also disclosed herein. 相似文献
3.
Hauck SI Cederberg C Doucette A Grosser L Hales NJ Poon G Gravestock MB 《Bioorganic & medicinal chemistry letters》2007,17(2):337-340
Substitution of phenyl oxazolidinones with carbon-linked azoles resulted in the discovery of a new class of potent oxazolidinones that have excellent Gram-positive activity. In addition, replacement of the C-5 acetamide side chains with a 4-methyl triazole diminished monoamine oxidase activity. The synthesis and biological evaluation of these compounds are reported. 相似文献
4.
Kim SJ Kim SJ Jung MH Yoo KH Cho JH Oh CH 《Bioorganic & medicinal chemistry letters》2008,18(21):5815-5818
The synthesis of a new series of oxazolidinones having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound 15g having [1,2,5]thiadiazolidin-1,1-dioxide moiety showed the most potent antibacterial activity. 相似文献
5.
So-Young Kim Hyeong Beom Park Jung-Hyuck Cho Kyung Ho Yoo Chang-Hyun Oh 《Bioorganic & medicinal chemistry letters》2009,19(9):2558-2561
The synthesis of a new series of oxazolidinones having spiro[2,4]heptane moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound Ih having fluoro group showed the most potent antibacterial activity. 相似文献
6.
A new series of N-linked 5-triazolylmethyl oxazolidinones with varying substitution at the piperazine nitrogen 4-position were synthesized and tested against a panel of Gram-positive and Gram-negative bacteria including clinical isolates. Most of the compounds showed excellent antibacterial activity against susceptible and resistant Gram-positive organisms. One of the compounds showed enhanced antibacterial activity against Moraxella catarrhalis. 相似文献
7.
A series of oxazolidinone derivatives carrying sulphonyl group was synthesized and their antibacterial activity was evaluated in vitro. Many of such compounds demonstrated potent antibacterial activity. The activity of a novel compound (YC-20) was 2-4-fold more potent than that of linezolid. 相似文献
8.
Ji-Young Kim Frederick E. Boyer Allison L. Choy Michael D. Huband Paul J. Pagano J.V.N. Vara Prasad 《Bioorganic & medicinal chemistry letters》2009,19(2):550-553
A novel series of oxazolidinones were synthesized in which the morpholine C-ring of linezolid was replaced with homomorpholine. In addition to investigating the effect of a homomorpholine C-ring on antibacterial activity, the effect of des-, mono-, di-, and tri-fluoro substitution on the phenyl B-ring was investigated as well. Various C-5 functional groups were also examined, including acetamides and triazoles and carboxamides. 相似文献
9.
Ciske FL Barbachyn MR Genin MJ Grega KC Lee CS Dolak LA Seest EP Watt W Adams WJ Friis JM Ford CW Zurenko GE 《Bioorganic & medicinal chemistry letters》2003,13(23):4235-4239
The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed. 相似文献
10.
Takhi M Singh G Murugan C Thaplyyal N Maitra S Bhaskarreddy KM Amarnath PV Mallik A Harisudan T Trivedi RK Sreenivas K Selvakumar N Iqbal J 《Bioorganic & medicinal chemistry letters》2008,18(18):5150-5155
Novel oxazolidinone antibacterials bearing a variety of 3-indolylglyoxamide substituents have been explored in an effort to improve the spectrum and potency of this class of agents. A subclass of this series was also made with the diversity at C-5 terminus. These derivatives have been screened against a panel of clinically relevant Gram-positive pathogens and fastidious Gram-negative organisms. Several analogs in this series were identified with in vitro activity superior to linezolid (MIC=0.25-2 microg/mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC=2-4 microg/mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model. 相似文献
11.
Wahab Khan M Jahangir Alam M Rashid MA Chowdhury R 《Bioorganic & medicinal chemistry》2005,13(16):4796-4805
Two series of 2-substituted and three new diacetyl benzofurans were synthesized through palladium-catalyzed reactions and their in vitro antimicrobial spectra were assessed. The compounds demonstrated mild to significant growth inhibition against antibiotic-susceptible standard and clinically isolated strains of Gram-positive and Gram-negative bacteria as well as human fungal pathogens. Ampicillin and kanamycin were used as references for antibacterial screening; nystatin and amphotericin B were used for antifungal screening. Varying substitution at the benzofuran moiety and subsequent antimicrobial screening identified the C-3-acetyl functionality as a new structural alternative for optimal antimicrobial property in the benzofuran class of compounds. 相似文献
12.
A series of novel acylide derivatives have been synthesized from erythromycin A via a facile procedure. By applying this procedure, cyclic carbonation to C-11,12 position, acylation to C-3 hydroxyl, and deprotection provided the desired acylides. These compounds showed antibacterial activity against both macrolide-susceptible strains and macrolide-resistant strains. Because of existence of 6-O-allyl substitution, these derivatives can be used as intermediates for further structural modification. 相似文献
13.
Bobkova EV Yan YP Jordan DB Kurilla MG Pompliano DL 《The Journal of biological chemistry》2003,278(11):9802-9807
Kinetic analysis of ribosomal peptidyltransferase activity in a methanolic puromycin reaction with wild type and drug-resistant 23 S RNA mutants was used to probe the structural basis of catalysis and mechanism of resistance to antibiotics. 23 S RNA mutants G2032A and G2447A are resistant to oxazolidinones both in vitro and in vivo with the latter displaying a 5-fold increase in the value of Km for initiator tRNA and a 100-fold decrease in Vmax in puromycin reaction. Comparison of the Ki values for oxazolidinones, chloramphenicol, and sparsomycin revealed partial cross-resistance between oxazolidinones and chloramphenicol; no cross-resistance was observed with sparsomycin, a known inhibitor of the peptidyltransferase A-site. Inhibition of the mutants using a truncated CCA-Phe-X-Biotin fragment as a P-site substrate is similar to that observed with the intact initiator tRNA, indicating that the inhibition is substrate-independent and that the peptidyltransferase itself is the oxazolidinone target. Mapping of all known mutations that confer resistance to these drugs onto the spatial structure of the 50 S ribosomal subunit allows for docking of an oxazolidinone into a proposed binding pocket. The model suggests that oxazolidinones bind between the P- and A-loops, partially overlapping with the peptidyltransferase P-site. Thus, kinetic, mutagenesis, and structural data suggest that oxazolidinones interfere with initiator fMet-tRNA binding to the P-site of the ribosomal peptidyltransferase center. 相似文献
14.
Quesnelle CA Gill P Roy S Dodier M Marinier A Martel A Snyder LB D'Andrea SV Bronson JJ Frosco M Beaulieu D Warr GA Denbleyker KL Stickle TM Yang H Chaniewski SE Ferraro CA Taylor D Russell JW Santone KS Clarke J Drain RL Knipe JO Mosure K Barrett JF 《Bioorganic & medicinal chemistry letters》2005,15(11):2728-2733
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds. 相似文献
15.
Thomasco LM Gadwood RC Weaver EA Ochoada JM Ford CW Zurenko GE Hamel JC Stapert D Moerman JK Schaadt RD Yagi BH 《Bioorganic & medicinal chemistry letters》2003,13(23):4193-4196
Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds. 相似文献
16.
Nomura T Iwaki T Yasukata T Nishi K Narukawa Y Uotani K Hori T Miwa H 《Bioorganic & medicinal chemistry》2005,13(24):6615-6628
A new type of ketolides, bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and a cyclic carbonate at the C-11,12 position was prepared and the antibacterial activities of the compounds were evaluated. Some of the derivatives showed potent antibacterial activity against both Haemophilus influenzae and Streptococcus pneumoniae, which are clinically important respiratory tract pathogens. Among the derivatives prepared, compound 5s with a quinolin-4-yl moiety was found to have potent and well-balanced activity against S. pneumoniae and H. influenzae including erythromycin-resistant strains. 相似文献
17.
Linezolid (formerly U-100766) and eperezolid (formerly U-100592) are novel oxazolidinone antimicrobial agents that are active against multi-drug-resistant staphylococci, streptococci, enterococci, corynebacteria, and mycobacteria. Preliminary studies also demonstrated that the compounds inhibited some test strains of anaerobic bacteria. Therefore, we extended the in vitro evaluation of these agents to include a total of 54 different anaerobic species. Minimal inhibitory concentration (MIC) values were determined using a standard agar dilution method for 143 anaerobic bacterial isolates. Eperezolid and linezolid demonstrated potent activity against the anaerobic Gram-positive organisms with most MIC values in the range of 0.25-4 microg/mL. Viridans streptococci demonstrated MICs of 1-2 microg/mL; Peptostreptococcus species and Propionibacterium species were inhibited by =0.25-1 microg/mL. Clostridial species were generally susceptible to the oxazolidinones (MICs of =0.25-8 microg/mL); however, seven strains of Clostridium difficile with linezolid MICs of 16 microg/mL or greater were detected. Against the anaerobic Gram-negative organisms, linezolid was more potent than eperezolid, especially for Bacteroides species. Linezolid inhibited most bacteroides in the range of 2-8 microg/mL, while eperezolid was generally two- to eight-fold less active. Linezolid and eperezolid both demonstrated potent activity against Fusobacterium species,Mobiluncus species,Prevotella intermedia, and Porphyromonas asaccharolytica (MICs of =0.25-0.5 microg/mL). Overall, the oxazolidinones demonstrated a significant level of activity against a number of clinically-important anaerobic bacterial species. Linezolid may potentially provide a broader spectrum of anaerobic coverage than eperezolid due to its greater activity against Bacteroides species. 相似文献
18.
Leach KL Swaney SM Colca JR McDonald WG Blinn JR Thomasco LM Gadwood RC Shinabarger D Xiong L Mankin AS 《Molecular cell》2007,26(3):393-402
The oxazolidinones are one of the newest classes of antibiotics. They inhibit bacterial growth by interfering with protein synthesis. The mechanism of oxazolidinone action and the precise location of the drug binding site in the ribosome are unknown. We used a panel of photoreactive derivatives to identify the site of action of oxazolidinones in the ribosomes of bacterial and human cells. The in vivo crosslinking data were used to model the position of the oxazolidinone molecule within its binding site in the peptidyl transferase center (PTC). Oxazolidinones interact with the A site of the bacterial ribosome where they should interfere with the placement of the aminoacyl-tRNA. In human cells, oxazolidinones were crosslinked to rRNA in the PTC of mitochondrial, but not cytoplasmic, ribosomes. Interaction of oxazolidinones with the mitochondrial ribosomes provides a structural basis for the inhibition of mitochondrial protein synthesis, which is linked to clinical side effects associated with oxazolidinone therapy. 相似文献
19.
Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors. 总被引:5,自引:1,他引:4 下载免费PDF全文
N B Matassova M V Rodnina R Endermann H P Kroll U Pleiss H Wild W Wintermeyer 《RNA (New York, N.Y.)》1999,5(7):939-946
Oxazolidinones are antibacterial agents that act primarily against gram-positive bacteria by inhibiting protein synthesis. The binding of oxazolidinones to 70S ribosomes from Escherichia coli was studied by both UV-induced cross-linking using an azido derivative of oxazolidinone and chemical footprinting using dimethyl sulphate. Oxazolidinone binding sites were found on both 30S and 50S subunits, rRNA being the only target. On 16S rRNA, an oxazolidinone footprint was found at A864 in the central domain. 23S rRNA residues involved in oxazolidinone binding were U2113, A2114, U2118, A2119, and C2153, all in domain V. This region is close to the binding site of protein L1 and of the 3' end of tRNA in the E site. The mechanism of action of oxazolidinones in vitro was examined in a purified translation system from E. coli using natural mRNA. The rate of elongation reaction of translation was decreased, most probably because of an inhibition of tRNA translocation, and the length of nascent peptide chains was strongly reduced. Both binding sites and mode of action of oxazolidinones are unique among the antibiotics known to act on the ribosome. 相似文献
20.
Yamamoto H Terasawa T Nakamura A Kawabata K Sakane K Matsumoto S Matsumoto Y Tawara S 《Bioorganic & medicinal chemistry》2000,8(5):1159-1170
A series of 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamid o]cephalosporins having a pyridine ring connected through various spacer moieties at the C-3 position was designed and synthesized and evaluated for antibacterial activity and oral absorption in rats. All compounds showed potent antibacterial activity against Staphylococcus aureus, whereas antibacterial activity against gram-negative bacteria was markedly influenced by the spacer moiety between the pyridine and cephem nucleus. Oral absorption was influenced by the position of the pyridine nitrogen as well as by the spacer moiety. Among these compounds, FR86830 (14), having a 4-pyridylmethylthio moiety at the C-3 position, showed the most well balanced activity and moderate oral absorption. 相似文献