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Hiroaki Mitsuya - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of potent hiv 1 protease inhibitors containing bicyclic Oxazolidinone scaffold as the p2 ligands structure activity studies and biological and x ray structural studies
Journal of Medicinal Chemistry, 2018Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hiroaki Mitsuya, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro HattoriAbstract:We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic Oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic Oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 A resolution, respectively, and revealed important interactions in the active site that have not yet been explored.
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Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies
2018Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro Hattori, Hiroaki MitsuyaAbstract:We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic Oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic Oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored
Yushe Yang - One of the best experts on this subject based on the ideXlab platform.
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solubility driven optimization of pyridin 3 yl benzoxazinyl Oxazolidinones leading to a promising antibacterial agent
Journal of Medicinal Chemistry, 2013Co-Authors: Bin Guo, Houxing Fan, Qisheng Xin, Wenjing Chu, Hui Wang, Yanqin Huang, Xiaoyan Chen, Yushe YangAbstract:The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-Oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-Oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure–activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold bett...
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solubility driven optimization of pyridin 3 yl benzoxazinyl Oxazolidinones leading to a promising antibacterial agent
Journal of Medicinal Chemistry, 2013Co-Authors: Bin Guo, Houxing Fan, Qisheng Xin, Wenjing Chu, Hui Wang, Yanqin Huang, Xiaoyan Chen, Yushe YangAbstract:The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-Oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-Oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid.
Bin Guo - One of the best experts on this subject based on the ideXlab platform.
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solubility driven optimization of pyridin 3 yl benzoxazinyl Oxazolidinones leading to a promising antibacterial agent
Journal of Medicinal Chemistry, 2013Co-Authors: Bin Guo, Houxing Fan, Qisheng Xin, Wenjing Chu, Hui Wang, Yanqin Huang, Xiaoyan Chen, Yushe YangAbstract:The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-Oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-Oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure–activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold bett...
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solubility driven optimization of pyridin 3 yl benzoxazinyl Oxazolidinones leading to a promising antibacterial agent
Journal of Medicinal Chemistry, 2013Co-Authors: Bin Guo, Houxing Fan, Qisheng Xin, Wenjing Chu, Hui Wang, Yanqin Huang, Xiaoyan Chen, Yushe YangAbstract:The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-Oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-Oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid.
Dean L Shinabarger - One of the best experts on this subject based on the ideXlab platform.
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in vitro activity of tr 700 the antibacterial moiety of the prodrug tr 701 against linezolid resistant strains
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Karen Joy Shaw, Dean L Shinabarger, Ronda D. Schaadt, S Poppe, Vickie Browndriver, John T Finn, Chris M Pillar, Gary E ZurenkoAbstract:TR-701 is the orally active prodrug of TR-700, a novel Oxazolidinone that demonstrates four- to eightfoldgreater activity than linezolid (LZD) against Staphylococcus and Enterococcus spp. In this study evaluating the in vitro sensitivity of LZD-resistant isolates, TR-700 demonstrated 8- to 16-fold-greater potency than LZD against all strains tested, including methicillin-resistant Staphylococcus aureus (MRSA), strains of MRSA carrying the mobile cfr methyltransferase gene, and vancomycin-resistant enterococci. The MIC90 for TR-700 against LZD-resistant S. aureus was 2 g/ml, demonstrating the utility of TR-700 against LZD-resistant strains. A model of TR-700 binding to 23S rRNA suggests that the increased potency of TR-700 is due to additional target site interactions and that TR-700 binding is less reliant on target residues associated with resistance to LZD. Oxazolidinone antibiotics are one of the newest classes of antibiotics developed within the past 30 years, with linezolid (LZD) representing the only marketed member of this class. In 2000, LZD (Zyvox) was granted approval for the treatment of infections associated with vancomycin-resistant Enterococcus faecium, nosocomial pneumonia, community-acquired pneumonia due to Streptococcus pneumoniae and methicillin-sensitive Staphylococcus aureus (MSSA), and complicated skin and skin structure infections, including cases due to methicillinresistant Staphylococcus aureus (MRSA) (1). Later approvals included pediatric use, pneumonia due to multidrugresistant S. pneumoniae, and treatment of diabetic foot infections, without osteomyelitis, caused by gram-positive bacteria. These approvals represent important milestones for the novel Oxazolidinone class in the treatment of serious infections. Oxazolidinones have been shown to bind to the 50S ribosomal subunit and inhibit protein translation (31). A model of the binding of LZD to the 23S rRNA peptidyl transferase region has been previously published, based upon in vivo crosslinking experiments (18). This model predicts that LZD would specifically interfere with the binding of the amino acid portion of the aminoacyl tRNA to the ribosomal A site. The recent crystal structure of LZD bound to the 50S ribosomal subunit confirms these findings and suggests that the mechanism of inhibition involves competition with the incoming A site substrates (13). Mutations in the 23S rRNA central loop of domain V, the peptidyl transferase center (PTC), are associated with the development of LZD resistance. LZD-resistant S. aureus, Staphylococcus epidermidis, Enterococcus faecium, and Enterococcus faecalis mutants have been isolated infrequently in the clinic and can be selected for in the
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Oxazolidinone Antibiotics Target the P Site on Escherichia coli Ribosomes
Antimicrobial agents and chemotherapy, 2002Co-Authors: Hiroyuki Aoki, Dean L Shinabarger, Susan M. Poppe, Toni J. Poel, Elizabeth A. Weaver, Robert C. Gadwood, Richard C. Thomas, M. Clelia GanozaAbstract:The Oxazolidinones are a novel class of antimicrobial agents that target protein synthesis in a wide spectrum of gram-positive and anaerobic bacteria. The Oxazolidinone PNU-100766 (linezolid) inhibits the binding of fMet-tRNA to 70S ribosomes. Mutations to Oxazolidinone resistance in Halobacterium halobium, Staphylococcus aureus, and Escherichia coli map at or near domain V of the 23S rRNA, suggesting that the Oxazolidinones may target the peptidyl transferase region responsible for binding fMet-tRNA. This study demonstrates that the potency of Oxazolidinones corresponds to increased inhibition of fMet-tRNA binding. The inhibition of fMet-tRNA binding is competitive with respect to the fMet-tRNA concentration, suggesting that the P site is affected. The fMet-tRNA reacts with puromycin to form peptide bonds in the presence of elongation factor P (EF-P), which is needed for optimum specificity and efficiency of peptide bond synthesis. Oxazolidinone inhibition of the P site was evaluated by first binding fMet-tRNA to the A site, followed by translocation to the P site with EF-G. All three of the Oxazolidinones used in this study inhibited translocation of fMet-tRNA. We propose that the Oxazolidinones target the ribosomal P site and pleiotropically affect fMet-tRNA binding, EF-P stimulated synthesis of peptide bonds, and, most markedly, EF-G-mediated translocation of fMet-tRNA into the P site.
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Oxazolidinone resistance mutations in 23s rrna of escherichia coli reveal the central region of domain v as the primary site of drug action
Journal of Bacteriology, 2000Co-Authors: Liqun Xiong, Dean L Shinabarger, Patricia Kloss, Stephen Douthwaite, Niels Moller Andersen, Steven Swaney, Alexander S MankinAbstract:Oxazolidinone antibiotics inhibit bacterial protein synthesis by interacting with the large ribosomal subunit. The structure and exact location of the Oxazolidinone binding site remain obscure, as does the manner in which these drugs inhibit translation. To investigate the drug-ribosome interaction, we selected Escherichia coli Oxazolidinone-resistant mutants, which contained a randomly mutagenized plasmid-borne rRNA operon. The same mutation, G2032 to A, was identified in the 23S rRNA genes of several independent resistant isolates. Engineering of this mutation by site-directed mutagenesis in the wild-type rRNA operon produced an Oxazolidinone resistance phenotype, establishing that the G2032A substitution was the determinant of resistance. Engineered U and C substitutions at G2032, as well as a G2447-to-U mutation, also conferred resistance to Oxazolidinone. All the characterized resistance mutations were clustered in the vicinity of the central loop of domain V of 23S rRNA, suggesting that this rRNA region plays a major role in the interaction of the drug with the ribosome. Although the central loop of domain V is an essential integral component of the ribosomal peptidyl transferase, Oxazolidinones do not inhibit peptide bond formation, and thus these drugs presumably interfere with another activity associated with the peptidyl transferase center.
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The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Steve M. Swaney, M. Clelia Ganoza, Hiroyuki Aoki, Dean L ShinabargerAbstract:The Oxazolidinones represent a new class of antimicrobial agents which are active against multidrug-resistant staphylococci, streptococci, and enterococci. Previous studies have demonstrated that Oxazolidinones inhibit bacterial translation in vitro at a step preceding elongation but after the charging of N-formylmethionine to the initiator tRNA molecule. The event that occurs between these two steps is termed initiation. Initiation of protein synthesis requires the simultaneous presence of N-formylmethionine-tRNA, the 30S ribosomal subunit, mRNA, GTP, and the initiation factors IF1, IF2, and IF3. An initiation complex assay measuring the binding of [3H]N-formylmethionyl-tRNA to ribosomes in response to mRNA binding was used in order to investigate the mechanism of Oxazolidinone action. Linezolid inhibited initiation complex formation with either the 30S or the 70S ribosomal subunits from Escherichia coli. In addition, complex formation with Staphylococcus aureus 70S tight-couple ribosomes was inhibited by linezolid. Linezolid did not inhibit the independent binding of either mRNA or N-formylmethionyl-tRNA to E. coli 30S ribosomal subunits, nor did it prevent the formation of the IF2–N-formylmethionyl-tRNA binary complex. The results demonstrate that Oxazolidinones inhibit the formation of the initiation complex in bacterial translation systems by preventing formation of the N-formylmethionyl-tRNA–ribosome–mRNA ternary complex.
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Mechanism of Action of Oxazolidinones: Effects of Linezolid and Eperezolid on Translation Reactions
Antimicrobial agents and chemotherapy, 1997Co-Authors: Dean L Shinabarger, Steve M. Swaney, Alice H Lin, Keith R Marotti, Robert W. Murray, Earline P. Melchior, Donna S. Dunyak, William F. Demyan, Jerry M. BuysseAbstract:The Oxazolidinones are a new class of synthetic antibiotics with good activity against gram-positive pathogenic bacteria. Experiments with a susceptible Escherichia coli strain, UC6782, demonstrated that in vivo protein synthesis was inhibited by both eperezolid (formerly U-100592) and linezolid (formerly U-100766). Both linezolid and eperezolid were potent inhibitors of cell-free transcription-translation in E. coli, exhibiting 50% inhibitory concentrations (IC50s) of 1.8 and 2.5 microM, respectively. The ability to demonstrate inhibition of in vitro translation directed by phage MS2 RNA was greatly dependent upon the amount of RNA added to the assay. For eperezolid, 128 microg of RNA per ml produced an IC50 of 50 microM whereas a concentration of 32 microg/ml yielded an IC50 of 20 microM. Investigating lower RNA template concentrations in linezolid inhibition experiments revealed that 32 and 8 microg of MS2 phage RNA per ml produced IC50s of 24 and 15 microM, respectively. This phenomenon was shared by the translation initiation inhibitor kasugamycin but not by streptomycin. Neither Oxazolidinone inhibited the formation of N-formylmethionyl-tRNA, elongation, or termination reactions of bacterial translation. The Oxazolidinones appear to inhibit bacterial translation at the initiation phase of protein synthesis.
Troels Skrydstrup - One of the best experts on this subject based on the ideXlab platform.
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importance of c n bond rotation in n acyl Oxazolidinones in their smi2 promoted coupling to acrylamides
Journal of the American Chemical Society, 2009Co-Authors: Rolf H Taaning, Karl B Lindsay, Birgit Schiott, Kim Daasbjerg, Troels SkrydstrupAbstract:A detailed mechanistic investigation was undertaken to determine the dominating factors of the postelectron transfer steps in the SmI2-promoted carbon−carbon bond forming reaction between N-acyl Oxazolidinones and acrylamides. Competition experiments were performed by reacting two N-acyl Oxazolidinones with a limiting amount of N-t-butyl acrylamide, and from the product distribution, the relative reactivity values (RV) for a series of N-acyl Oxazolidinones were then calculated against N-pivaloyl Oxazolidinone as the reference. An almost linear correlation was obtained for the simple alkyl N-acyl Oxazolidinones when ln RV was plotted against the activation barriers for C−N bond rotation (s-trans to s-cis) obtained by DFT calculations, implying that C−N bond rotation from the s-trans to s-cis conformation is one of the essential parameters controlling the reactivity. These results were substantiated by other competition experiments carried out for the corresponding imide derivatives, where rotation is not n...
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smi2 promoted intra and intermolecular c c bond formation with chiral n acyl Oxazolidinones
ChemInform, 2009Co-Authors: Rolf H Taaning, Laura Thim, Jacob Karaffa, Araceli G Campana, Annamette Hansen, Troels SkrydstrupAbstract:Abstract The suitability of chiral Oxazolidinones in the SmI2-mediated C–C bond generation between the imide functionality of an N-acyl Oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon–carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl Oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5-exo-trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.
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smi2 promoted radical addition reactions with n 2 indolylacyl Oxazolidinones synthesis of bisindole compounds
Journal of Organic Chemistry, 2007Co-Authors: Karl B Lindsay, Francesc Ferrando, Kasper L Christensen, Jacob Overgaard, Tomas Roca, Lluisa M Bennasar, Troels SkrydstrupAbstract:The treatment of N-acyl Oxazolidinones of N-benzyl 2-indolecarboxylic acids varying in the substitution pattern of the indole ring with samarium diiodide at −78 °C led to the formation of two indole dimer products. The major product isolated in yields from 55 to 59% represents an unsymmetrical dimer arising from 1,4-addition to the 2-indolecarboxylic acid derivative of a possible ketyl-type radical anion intermediate originating from the reduction of the exocyclic carbonyl group of the N-acyl Oxazolidinone. The minor dimer, represented by a symmetrical diketone, was produced in yields ranging from 11 to 23%. Even in the presence of an α,β-unsaturated amide, dimerization was the preferred pathway rather than the formation of a γ-keto amide. Upon treatment with acid, the unsymmetrical indole dimer cyclized to form a diindolequinone. Finally, the N-acyl Oxazolidinones of pyrrole-2-carboxylic acid and 3-indolecarboxylic acid preferred in both cases to undergo C−C bond formation with an acrylamide in the prese...
