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The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators

The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.

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Top Picks: new discover of 1,1-Dioxo-isothiazolidine

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Discovery, synthesis, and structure-activity relationship development of a series of N -4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4) with oral efficacy in an antiparkinsonian animal model

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl) phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.

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The Absolute Best Science Experiment for 2682-49-7

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2-Thiazolidinone derivatives, pharmaceutical compositions containing them, process for preparing same, and use

The present invention relates to novel 2-thiazolidi-none derivatives of the general formula (I), wherein, A stands for hydrogen, halogen or a C1 4alkyl, C1 4alkoxy or nitro group; and, n is 0 or 1. The compounds according to the invention show a cytoprotective and gastric acid secretion-inhibiting effect and thus, may be used in the therapy of gastric and duodenal ulcers. The invention includes preparation methods for the above compounds with the general formula (I) and pharmaceutical compositions containing them.

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Extended knowledge of Thiazolidin-2-one

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Discovery of a COX-2 selective inhibitor hit with anti-inflammatory activity and gastric ulcer protective effect

Aim: A novel series of 2-arylimino-5-arylidenethiazolidin-4-ones 12a-n were synthesized and all the target compounds were fully characterized by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis. Materials & methods: All the target compounds were evaluated for their COX inhibition by enzyme immunoassay kit and in vivo anti-inflammatory activity. Results: Tested compounds were found more potent inhibitors of COX-2 (IC50 = 0.54-3.14 M) than COX-1 (IC50 = 4.97-11.52 M). The ulcerogenic liability of compounds 12(d, e, f, h, k, m) was performed and showed gastric safety more than or comparable to celecoxib. Conclusion: In addition, docking study of the most potent and selective compound 12h into COX-2 active site revealed that this target compound assumed interactions and binding pattern similar to that of as a cocrystallized ligand bromocelecoxib (S-58).

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Archives for Chemistry Experiments of Thiazolidin-2-one

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Ruthenium-catalyzed synthesis of vinylamides at low acetylene pressure

The reaction of cyclic amides with acetylene under low pressure, using ruthenium-phosphine catalysts, afforded a broad variety ofN-vinylated amides including (azabicyclic) lactams, oxazolidinones, benzoisoxazolones, isoindolinones, quinoxalinones, oxazinanones, cyclic urea derivatives (imidazolidinones), nucleobases (thymine), amino acid anhydrides and thiazolidinone.

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Archives for Chemistry Experiments of Thiazolidin-2-one

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Synthesis and in vitro anti-breast cancer evaluation of some novel benzimidazole ?pyridine conjugates

A new series of benzimidazole bearing pyridine derivatives were synthesized by condensation of 1,2-phenylenediamine with 2-oxo-1,2-dihydro-pyridine-3-carboxylic acid derivative 2 in phosphoric acid to give 3-(1Hbenzo[ d]imidazol-2-yl)-pyridin-2(1H)-one derivative 3. Compound 3 on further reaction with a mixture of phosphorus oxychloride and phosphorus pentachloride gave 2-(2-chloro-) pyridin-3-yl)-1H-benzo[d] imidazole derivative 4. Moreover, 4 were reacted with different amines to give 3-(1H-benzo[d]imidazol-2-yl)-N-(substituted) pyridin-2-amine derivatives 5a-c. Meanwhile, N-(N-(substituted) sulfamoyl) pyridin-3-yl)-1H-benzo[d]imidazole-1-carboxamide derivatives 7a,b were synthesized by reaction of 5c with chlorosulfonyl isocyanate to give 2-(pyridin-3-yl)-1H-benzo [d]imidazole-1-carbonyl) sulfamoyl chloride derivative followed by reaction of the latter with different amines. On the other hand, upon treatment compound 4 with hydrazine hydrate gave the hydrazide derivative 8. The reaction of compound 8 with different alkyl/arylisothiocyanates gave the corresponding thiosemicarbazide derivatives 9a-d, while their cyclo condensation reaction with ethyl chloro acetate gave the corresponding thiazolidin-4-one derivatives 10a-c. Moreover, condensation of 10a,c with aromatic aldehydes afforded the corresponding 5-arylidine-thiazolidin-4-one derivatives 11a,b. Cytotoxic evaluation of some of the newly synthesized compounds against human breast carcinoma cell line MCF-7 revealed that, these compounds showed promising activity compared with Doxorubicin as positive control.

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More research is needed about 4-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

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Effect of substituents in the syntheses of phenyl-substituted dibenzonaphthyridines

A facile and elegant syntheses of linear and angular phenyl-substituted dibenzonaphthyridines from 2,4-dichloroquinolines through anilinoquinolines have been developed. The substituents in the 4th position of the anilinoquinoline and the temperature were found to play a vital role in the regulation of the yield towards the synthesis of the final compounds. The methyl group in the 7th position of the naphthyridin-11-ones was found to hinder the N-methylation reaction sterically, consequently increasing the reaction time than other derivatives.

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The Absolute Best Science Experiment for (R)-2-Oxothiazolidine-4-carboxylic acid

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Electric Literature of 19771-63-2, Catalysts function by providing an alternate reaction mechanism that has a lower activation energy than would be found in the absence of the catalyst. In some cases, the catalyzed mechanism may include additional steps.In a article, 19771-63-2, molcular formula is C4H5NO3S, introducing its new discovery.

Pharmacokinetics of 2-oxothiazolidine-4-carboxylate, a cysteine prodrug, and cysteine

The pharmacokinetics of both 2-oxothiazolidine-4-carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2- hour intravenous infusion (56-66 mg/kg) or similarly infused (70-100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis-Menten kinetics with parallel first-order elimination. OTZ was efficiently removed from the plasma. The Michaelis- Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.

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Advancement in the development of heterocyclic nucleosides for the treatment of cancer – A review

Cancer diseases are widely recognised as an important medical problem and killing millions of people in a year. Chemotherapeutic drugs are successful against cancer in many cases and different compounds, including the analogues of natural substances, may be used for anticancer agents. Nucleoside analogues also have become a necessity for the treatment of cancer diseases. Nucleoside, nucleotide and base analogues have been utilised for decades for the treatment of viral pathogens, neoplasms and in anticancer chemotherapy. This review focuses on the different types of nucleosides and their potential role as anticancer agents. It also discusses the nucleoside analogues approved by FDA and in process of approval. The effect of the substitution on the nucleoside analogues and their pharmacological role is also discussed in the review. Owing to the advances in computational chemistry, it concludes with the future advancement and possible outcome of the nucleoside analogues. Also, it depicts the development of heterocyclic nucleoside analogues, explores the QSAR of the synthesised compounds and discusses the 3 D QSAR pharmacophore modelling in order to examine their potential anti-cancer activities.

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Copper-catalyzed N-arylation of sulfonamides with aryl bromides under mild conditions

This Letter describes a copper catalyzed sulfonamide coupling reaction with aryl bromides to form N-aryl sulfonamides under mild conditions, including the first examples of Cu-catalyzed sulfonamide coupling at room temperature. The reaction protocol tolerates a broad range of substrates including a variety of primary and secondary sulfonamides and challenging heteroaryl bromides such as 2-bromothiazole.

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