- Novel nucleoside analogues targeting HCV replication through an NS5A-dependent inhibition mechanism
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A series of new tricyclic nucleosides were synthesized and evaluated as hepatitis C virus (HCV) replication inhibitors. Initial screening in a HCV replicon system, derived from a genotype 1b isolate, identified 9-benzylamino-3-(β-D-ribofuranosyl)-3H-imidazo[4′,5′:5,6]pyrido[2,3-b]pyrazine (15d) as the most potent analogue. Comparative assessment of 15d activity against HCV full-length viruses or subgenomic replicons derived from genotypes 1 to 4 revealed a specificity of the compound for genotypes 1 and 3. Surprisingly, resistance mutations selected against 15d were mapped to domains II and III of the non-structural protein 5A (NS5A), but not to the RNA-dependent RNA polymerase residing in NS5B. These results argue that compound 15d might represent a lead for the development of a novel class of NS5A inhibitors.
- Lougiakis, Nikolaos,Frakolaki, Efseveia,Karmou, Panagiota,Pouli, Nicole,Marakos, Panagiotis,Madan, Vanesa,Bartenschlager, Ralf,Vassilaki, Niki
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Read Online
- p38α AUTOPHOSPHORYLATION INHIBITORS
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The present invention concerns inhibitors of p38α autophosphorylation, pharmaceutical compositions comprising them, and their use in the treatment of a number of diseases, such as myocardial ischemia reperfusion injury. The inhibitors satisfy the following general formula: wherein R, R1, R2, R4, and R5 may have different meanings.
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- Synthesis method of aminopyridine compounds
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The invention provides a synthesis method of aminopyridine compounds. The synthesis method of the aminopyridine compounds comprises the following steps: under a heating condition, halogenated pyridineorganic matters and an ammoniation reagent are subjected to an ammoniation reaction to obtain an ammoniated product system, wherein in the ammoniation reaction, the temperature of the ammoniation reaction is 200-240 DEG C, and the ammoniation reagent is in a solid state and can be decomposed to generate ammonia gas; and the ammoniated product system is sequentially purified and salified to obtainthe aminopyridine compounds. The synthesis method does not need to add a solvent, so that the yield of three wastes can be greatly reduced; the type of the ammonification reagent and the ammonification reaction temperature are limited during the reaction process, such that the high reaction rate and the high conversion rate can be obtained without the addition of the catalyst, and the purification and salification process after the ammonification reaction is simple and has the good separation effect so as to substantially reduce the production cost and improve the product yield and the product purity. In addition, the synthesis method also has the advantages of good repeatability and the like.
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Paragraph 0055-0056
(2020/10/14)
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- Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators
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Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically validated, drug-like leads. In the present retro-metabolic drug design study, a series of 43 compounds were synthesized and characterized with regard to KV7.2/3 opening activity and efficacy. The most active compound 22d displays excellent potency (EC50 = 4 nM) and efficacy (154%) as a KV7.2/3 opener. Limited aqueous solubility hampered toxicity testing at concentrations higher than 63 μM, but this concentration was nontoxic to two hepatocellular cell lines (HEP-G2 and TAMH) in culture. The slightly less active but more soluble compound 25b (EC50 = 11 nM, efficacy 111%) showed an improved toxicity/activity ratio compared to flupirtine by three orders of magnitude and represents an attractive lead structure for the development of safer analgesics and antiepileptics.
- Surur, Abdrrahman S.,Bock, Christian,Beirow, Kristin,Wurm, Konrad,Schulig, Lukas,Kindermann, Markus K.,Siegmund, Werner,Bednarski, Patrick J.,Link, Andreas
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supporting information
p. 4512 - 4522
(2019/05/17)
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- A practical synthesis of substituted 2,6-diaminopyridines via microwave-assisted copper-catalyzed amination of halopyridines
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A microwave assisted copper-catalyzed amination protocol is reported utilizing a series of 2,6-dihalo- and 2-amino-6-halo pyridine precursors. Using this procedure, selective substitution of one or two halogens by aryl or alkylamines was achieved within 2-6 h with temperatures between 80 and 225 °C affording 2,6-diaminopyridines in good to excellent isolated yields. The reaction allows easy variation between educts and different N-substitutions. The target compounds are valuable precursors for the synthesis of bis-phosphorylated 2,6-diaminopyridines which are used as PNP pincer ligands in transition metal complexes.
- Mastalir, Matthias,Rosenberg, Egon E.,Kirchner, Karl
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p. 8104 - 8110
(2015/12/30)
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- OLIGOHETEROAROMATIC LUMINISCENT ASSEMBLIES AS HIGH-AFFINITY DNA SEQUENCE-DIRECTED LIGANDS
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The present invention provides a novel class of oligoheteroaromatic assemblies with luminescence characteristics and composition based on integrated polyheterocyclic polyamide oligomers of multiple nitrogen-containing heteroaromatic of the general formula (I) This novel class of compounds of the present invention is capable of binding to targeted DNA sequence in the minor groove, and thus is useful for genomics applications. In particular, the compounds of the invention binds to the DNA at a binding stoichiometry of 2: 1 ternary complexation with very high affinity and sequence selectivity.
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Page/Page column 39; 75
(2010/11/27)
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- Zinc-promoted direct amination of nitropyridines with methoxyamine via vicarious nucleophilic substitution
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Direct animation of nitropyridines with methoxyamine in the presence of a stoichiometric amount of zinc(II) chloride under basic conditions proceeds to give aminonitropyridines.
- Seko, Shinzo,Miyake, Kunihito
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p. 1519 - 1520
(2007/10/03)
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- Process for producing aminonitropyridines
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A process for producing an aminonitropyridine represented by the general formula [1], which comprises reacting a nitropyridine represented by the general formula [2] (wherein X1, X2 and X3 indicate a hydrogen atom, a halogen atom, a nitro group, a cyano group, an aryl group, an aromatic heterocycle or an alkyl group, etc.; Y is an oxygen atom; and n is 0 or 1) with an O-substituted hydroxylamine represented by the general formula [3] (wherein R4 is a hydrogen atom, an alkyl group, a cycloalkyl group or an aralkyl group; and R5 is an alkyl group or an aralkyl group) or a salt thereof in the presence of a base and a metal catalyst. STR1
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- Nitroketenaminals, VII: Synthesis of substituted 2-amino-3-nitropyridines from 1,3-biselectrophiles and 2-nitroethen-1,1-diamine
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The reaction of the enones 1a-f with the nitroketenaminal 2 leads to the 4,6-disubstituted 2-amino-1,4-dihydro-3-nitropyridines 3a-f. Compounds 3a-c,f are oxidized in low yields by air to the pyridines 4a-c,f.-5- and 6-substituted 2-amino-3-nitropyridines (9a,b and 11) can be prepared from 2, 8a,b, and 10, respectively.
- Troschutz,Luckel
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p. 785 - 789
(2007/10/02)
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- Regioselectivity of the Amination of Some 3-Nitropyridines by Liquid Ammonia / Potassium Permanganate
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3-Nitropyridine and some of its derivatives are aminated in a liquid ammonia solution of potassium permanganate to the corresponding 2- and (or) 4- and (or) 6-amino compounds.Quantumchemical calculations for a few 3-nitropyridines suggest that the experimentally observed regioselectivity of the amination is controlled by Coulombic interaction. --- Key Words: Amination / Nitropyridines / Reactivity indices / Calculations, MNDO
- Wozniak, Marian,Baranski, Andrzej,Szpakiewicz, Barbara
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p. 875 - 878
(2007/10/02)
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