- Debenzylative Sulfonylation of Tertiary Benzylamines Promoted by Visible Light
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An efficient, general, inexpensive, and environmentally friendly photosynthesis of sulfonamides via visible light promoted debenzylative sulfonylation of tertiary benzylamines is described. Compared to the traditional S?N coupling reactions, which are promoted by oxidative C?N bond cleavage of symmetrical tertiary alkylamines, this strategy provides a selective C?N bond cleavage protocol and avoids the use of transition-metal, explosive oxidants, and ligands.
- Fu, Ying,Wu, Qing-Kui,Du, Zhengyin
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p. 1896 - 1900
(2021/04/06)
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- A Broad-Spectrum Catalytic Amidation of Sulfonyl Fluorides and Fluorosulfates**
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A broad-spectrum, catalytic method has been developed for the synthesis of sulfonamides and sulfamates. With the activation by the combination of a catalytic amount of 1-hydroxybenzotriazole (HOBt) and silicon additives, amidations of sulfonyl fluorides and fluorosulfates proceeded smoothly and excellent yields were generally obtained (87–99 %). Noticeably, this protocol is particularly efficient for sterically hindered substrates. Catalyst loading is generally low and only 0.02 mol % of catalyst is required for the multidecagram-scale synthesis of an amantadine derivative. In addition, the potential of this method in medicinal chemistry has been demonstrated by the synthesis of the marketed drug Fedratinib via a key intermediate sulfonyl fluoride 13. Since a large number of amines are commercially available, this route provides a facile entry to access Fedratinib analogues for biological screening.
- Wei, Mingjie,Liang, Dacheng,Cao, Xiaohui,Luo, Wenjun,Ma, Guojian,Liu, Zeyuan,Li, Le
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supporting information
p. 7397 - 7404
(2021/02/16)
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- Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation
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In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure–activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1. The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.
- Belsuzarri, Masiel,Carson, Dennis A.,Chan, Michael,Chu, Paul J.,Corr, Maripat,Cottam, Howard B.,Hayashi, Tomoko,Lao, Fitzgerald S.,Nan, Jason,Saito, Tetsuya,Sato-Kaneko, Fumi,Shukla, Nikunj M.,Yao, Shiyin
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- VACCINE ADJUVANT
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Compounds useful as an adjuvant, e.g., formulas (I)-(VI) and uses thereof, for example, with immunogenic moieties or other adjuvants, are provided.
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Page/Page column 81-82
(2020/06/10)
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- Room Temperature Deoxyfluorination of Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and Tetramethylammonium Fluoride
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A method for the room temperature deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride and Me4NF is described. A large scope of aryl and heteroaryl substrates is demonstrated, and this method compares favorably to other common deoxyfluorination methods for many substrates.
- Melvin, Patrick R.,Ferguson, Devin M.,Schimler, Sydonie D.,Bland, Douglas C.,Sanford, Melanie S.
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supporting information
p. 1350 - 1353
(2019/03/08)
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- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
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The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
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supporting information
p. 8332 - 8338
(2013/12/04)
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- Building a sulfonamide library by eco-friendly flow synthesis
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A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.
- Gioiello, Antimo,Rosatelli, Emiliano,Teofrasti, Michela,Filipponi, Paolo,Pellicciari, Roberto
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supporting information
p. 235 - 239
(2013/06/27)
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- USE OF A COMPOUND CAPABLE OF REDUCING THE URIC ACID LEVEL FOR THE PREVENTION AND/OR THE TREATMENT OF LUNG INFLAMMATION AND FIBROSIS
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The present invention is directed to the use of a compound capable of reducing the uric acid level in a mammal for the prevention and/or the treatment of IL-1β driven lung pathology, particularly to treat lung inflammation such as chronic fibrosis, COPD and interstitial fibrosis and other IL-1β driven lung pathologies including those of autoimmune origin. Preferred compounds capable of reducing the uric acid level are selected from the group consisting of xanthine oxidase inhibitors, such as allopurinol, recombinant enzyme uricase and uricosuric compound capable of enhancing uric acid excretion, such as probenecid. The invention further relates to a method for identifying in vitro whether a patient presents an IL-1β driven lung pathology or is at risk to develop an IL-1β driven lung pathology, or for the screening of a compound for treating an IL-1β driven lung pathology.
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- Use of a compound capable of reducing the uric acid level for the prevention and/or the treatment of lung inflammation and fibrosis
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The present invention is directed to the use of a compound capable of reducing the uric acid level in a mammal for the prevention and/or the treatment of IL-1β driven lung pathology, particularly to treat lung inflammation such as chronic fibrosis, COPD and interstitial fibrosis and other IL-1β driven lung pathologies including those of autoimmune origin. Preferred compounds capable of reducing the uric acid level are selected from the group consisting of xanthine oxidase inhibitors, such as allopurinol, recombinant enzyme uricase and uricosuric compound capable of enhancing uric acid excretion, such as probenecid. The invention further relates to a method for identifying in vitro whether a patient presents an IL-1β driven lung pathology or is at risk to develop an IL-1β driven lung pathology.
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- Discovery and initial development of a novel class of antibacterials: Inhibitors of Staphylococcus aureus transcription/translation
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The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chemistry. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional solution phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8 μg/mL (compound 4l). Subsequent modification of the central aromatic ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a number of potent antibacterials with MICs of ≤1 μg/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one additional mechanism of action is operative.
- Larsen, Scott D.,Hester, Matthew R.,Craig Ruble,Kamilar, Gregg M.,Romero, Donna L.,Wakefield, Brian,Melchior, Earline P.,Sweeney, Michael T.,Marotti, Keith R.
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p. 6173 - 6177
(2007/10/03)
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- Rapid internal acyl migration and protein binding of synthetic probenecid glucuronides
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Internal acyl migration reactions of drug 1-O-acyl-β-D-glucopyranuronates (1β-acyl glucuronides) are of interest because of their possible role in covalent binding to proteins and consequent adverse effects. The reactivity of the synthetic probenecid 1β-acyl glucuronide (PRG), the principal metabolite of probenecid (PR) in humans, has been investigated in terms of acyl migration, hydrolysis, and covalent binding to proteins in phosphate buffer (pH 7.4) and human plasma at 37 °C. PRG primarily degraded by acyl migration according to apparent first-order kinetics and the 2-, 3-, and 4-acyl isomers sequentially appeared as both α- and β-anomeric forms. In addition, small amounts of PRG and extremely labile 1α-acyl isomer existed in the equilibrated mixture favoring the 2α/β-acyl isomer, that provided significant information regarding the mechanism of acyl migration. All of the positional isomers and anomers were characterized using preparative HPLC and NMR spectroscopy. Acyl migration was observed to predominate over hydrolysis in both media although the extent of hydrolysis in plasma was larger than that in the buffer. The overall degradation half-lives (h) in the buffer and plasma were 0.27 ± 0.003 and 0.17 ± 0.007, respectively. The covalent binding rapidly proceeded mainly via the Schiff's base mechanism and reached a plateau after 2 h of incubation. The maximal binding was 146 ± 4.8 pmol/mg of protein, and ca. 10% of the initial concentration of PRG. These results indicated that PRG is most labile and susceptible to acyl migration of all the drug acyl glucuronides reported to date in the physiological conditions, and highly reactive to plasma proteins, that could provide a possible explanation for the immunologically based adverse effects of PR.
- Akira, Kazuki,Uchijima, Takafumi,Hashimoto, Takao
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p. 765 - 772
(2007/10/03)
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- Benzothiazole derivatives with activity as adenosine receptor ligands
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The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.
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- Cleavage of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates
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The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates is reported. Amidomethyl esters are rapidly and quantitatively converted to the corresponding acid and secondary amide. Reactivity is inversely dependent upon the molar refractivity and lipophilicity of the ester, as well as with steric bulk in the carboxylic acid moiety. In contrast to chemical and plasma hydrolyses, no dependence upon the pK(a) of the carboxylate leaving group was observed, nor was there any dependence upon the amide N-substituent. The rate of decomposition was inhibited by the carboxylesterase inhibitor eserine but not by the cytochrome P450 inhibitor SKF-525A, indicating the involvement of esterases in the hydrolysis reaction. These results indicate that amidomethyl esters may be expected to be readily cleaved in vivo. Copyright (C) 1999 Elsevier Science B.V.
- Iley, Jim,Mendes, Eduarda,Moreira, Rui,Souza, Sofia
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p. 201 - 205
(2007/10/03)
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- Water dispersion containing ultrafine particles of organic compounds
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A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
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