51-20-7Relevant academic research and scientific papers
Carbonic anhydrase inhibitory properties of some uracil derivatives
Alper Türko?lu, Emir,?entürk, Murat,Supuran, Claudiu T.,Ekinci, Deniz
, p. 74 - 77 (2017)
Inhibitors of carbonic anhydrase (CA) have been carried out in many therapeutic applications, especially antiglaucoma activity. In this study, we investigated some uracil derivatives (4–12) to inhibit human CA I (hCA I) and II (hCA II) isoenzymes. The KI values of the compounds 4–12 are in the range of 0.085–428 μM for hCA I and of 0.1715–645 μM against hCA II, respectively. It is concluded from the kinetic investigations, all compounds used in the study act as competitive inhibitors with substrate, 4-NPA. Uracil derivatives are emerging agents for the inhibiton of carbonic anhydrase which could be used in biomedicine.
The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist
Moir, Michael,Lane, Samuel,Montgomery, Andrew P.,Hibbs, David,Connor, Mark,Kassiou, Michael
, (2020/12/21)
The development of selective CB2 receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB1 receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB2 receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB2R EC50 = 19 nM, CB1R EC50 > 10 μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
supporting information, p. 867 - 876 (2020/01/24)
Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
The synthesis and antituberculosis activity of 5-alkynyl uracil derivatives
Platonova, Yana B.,Tomilova, Larisa G.,Volov, Alexander N.
, (2020/06/26)
A series of new 5-alkynyl-substituted uracil and uridine derivatives were synthesised via palladium-catalysed Sonogashira cross-coupling reaction of 5-bromo-pyrimidine base with terminal acetylenes with good yields in DMF at room temperature. All obtained compounds were tested for antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis (H37Ra) at concentrations of 1–100 μg/ml using MABA test. Obtained results revealed that most of tested uracil derivatives exhibited high antimycobacterial activity (MIC50 = 1.1–19.2 μg/ml) in comparison with therapeutic agents such as rifampicin, isoniazid and D-cycloserine, excluding compounds having alkyl substituent at triple alkyne bond.
A 5 - bromo uracil preparation method
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Paragraph 0033-0040, (2019/10/04)
The invention discloses a preparation method for 5-bromouracil. By taking uracil as an initial raw material, sodium bromide and sodium hypochlorite as a green bromating agent, and water as a solvent, a mild brominating reaction is carried out under an acidic condition to obtain a high purity target product. The preparation method disclosed by the invention is green and environmental-friendly in synthetic process, convenient in post-treatment and suitable for large-scaled industrial production.
Inhibition of acetylcholinesterase and butyrylcholinesterase with uracil derivatives: kinetic and computational studies
Cavdar, Huseyin,Senturk, Murat,Guney, Murat,Durdagi, Serdar,Kayik, Gulru,Supuran, Claudiu T.,Ekinci, Deniz
, p. 429 - 437 (2019/01/14)
Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) inhibitors are interesting compounds for different therapeutic applications, among which Alzheimer’s disease. Here, we investigated the inhibition of these cholinesterases with uracil derivatives. The mechanism of inhibition of these enzymes was observed to be due to obstruction of the active site entrance by the inhibitors scaffold. Molecular docking and molecular dynamics (MD) simulations demonstrated the possible key interactions between the studied ligands and amino acid residues at different regions of the active sites of AChE and BuChE. Being diverse of the classical AChE and BuChE inhibitors, the investigated uracil derivatives may be used as lead molecules for designing new therapeutically effective enzyme inhibitors.
Preparation method for 5-bromouracil
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Paragraph 0025; 0026; 0030; 0032; 0034; 0036; 0042; 0044, (2018/08/04)
The invention discloses a preparation method for 5-bromouracil. According to the preparation method, uracil is used as a raw material and reacts with a bromination reagent under the action of acid oracid/anhydride, wherein the the bromination reagent is 1,3-dibromo-5,5-dimethylhydantoin; the acid/anhydride refers to a mixture of acid and anhydride; the acid or acid in the acid/anhydride is organic acid; and the anhydride is organic acid anhydride.
Preparation method for halogenated uracil compounds
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Paragraph 0046; 0047; 0050; 0052; 0054; 0056; 0068; 0070, (2018/08/04)
The invention discloses a preparation method for halogenated uracil compounds as shown in a formula 2 which is described in the specification. The preparation method comprises a step of subjecting a compound 1 and PCl5 to a chlorination reaction in a solvent. X in the formula is F, Cl, Br or I. The solvent is one or more selected from a group consisting of SOCl2, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene and 1,1,2-trichloroethane. The preparation method uses 5-halouracil as a starting material, and is simple in process, high in yield, friendly to environment and suitable for industrial production.
Solid-supported synthesis of N-alkylated derivatives of 5-bromo pyrimidine-2, 4-dione and Study of their cytotoxic effect
Sagheer, Tahira,Ehsan, Shahana,Akbar, Wajiha,Faisal, Saniya
, p. 742 - 748 (2018/07/15)
The presented study reports the synthesis of 5-bromo substituted pyrimidine-2,4-dione by conventional and solid-state microwave-assisted methodology. 5-bromo pyrimidine-2,4-dione derivatives represent the novel group of compounds possessing remarkable anti-tumor and antibacterial activities with significant therapeutic effects such as anti-neoplastic as well. Thus, a diversity-oriented convergent synthesis of complex organic molecules from simple and readily available substrates has been carried out that has resulted in the derivatization of 5-bromo pyrimidine-2,4 dione predominately giving N1 and N3 substituted compounds where R may be the alkyl, aryl, cyclohexyl methyl etc. In addition, use of solid-state microwave-assisted protocol proved to be of vital importance in terms of energy efficiency and designing a solvent-free ecofriendly synthetic route with considerably reduced reaction time.
Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925
Rafehi, Muhammad,Burbiel, Joachim C.,Attah, Isaac Y.,Abdelrahman, Aliaa,Müller, Christa E.
, p. 89 - 103 (2017/03/11)
The Gq protein-coupled, ATP- and UTP-activated P2Y2 receptor is a potential drug target for a range of different disorders, including tumor metastasis, inflammation, atherosclerosis, kidney disorders, and osteoporosis, but pharmacological studies are impeded by the limited availability of suitable antagonists. One of the most potent and selective antagonists is the thiouracil derivative AR-C118925. However, this compound was until recently not commercially available and little is known about its properties. We therefore developed an improved procedure for the synthesis of AR-C118925 and two derivatives to allow up-scaling and assessed their potency in calcium mobilization assays on the human and rat P2Y2 receptors recombinantly expressed in 1321N1 astrocytoma cells. The compound was further evaluated for inhibition of P2Y2 receptor-induced β-arrestin translocation. AR-C118925 behaved as a competitive antagonist with pA2 values of 37.2?nM (calcium assay) and 51.3?nM (β-arrestin assay). Selectivity was assessed vs. related receptors including P2X, P2Y, and adenosine receptor subtypes, as well as ectonucleotidases. AR-C118925 showed at least 50-fold selectivity against the other investigated targets, except for the P2X1 and P2X3 receptors which were blocked by AR-C118925 at concentrations of about 1?μM. AR-C118925 is soluble in buffer at pH 7.4 (124?μM) and was found to be metabolically highly stable in human and mouse liver microsomes. In Caco2 cell experiments, the compound displayed moderate permeability indicating that it may show limited peroral bioavailability. AR-C118925 appears to be a useful pharmacological tool for in vitro and in vivo studies.
