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Analytical Studies on Isoxazoles. I. A New Colorimetric Determination of 5-Substituted 3-Isoxazolecarboxylic Acids and Their Derivatives

A new colorimetric method for the determination of 5-methyl-3-isoxazolecarboxylic acid (MIA) and 5-phenyl-3-isoxazolecarboxylic acid (PIA) was established.This method is based on the decomposition of 5-substituted 3-isoxazolecarboxylic acids to their corresponding beta-ketonitriles, followed by condensation with p-dimethylaminobenzaldehyde (DABA).The 5-carboxylic isomers caused no interference in the determination of MIA and PIA.Further applications of this method to peroxisal (II), N-<(dimethylamino)carbonyl>-5-methyl-3-isoxazolecarboxamide (III), and 3-(2-oxazolin-2-yl)-5-methylisoxazole (IV), by decomposition to the corresponding 5-substituted 3-isoxazolecarboxylic acids, followed by the color reaction with DABA, are described.Keywords-colorimetric determination; 3-isoxazolecarboxylic acids; p-dimethylaminobenzaldehyde; Knoevenagel condensation reaction; alpha-benzoyl-p-dimethylaminocinnamonitrile; alpha-acetyl-p-dimethylaminocinnamonitrile.

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Synthesis of imides by palladium-catalyzed C-H functionalization of aldehydes with secondary amides

An efficient palladium-catalyzed C-H functionalization of aldehydes with various N-substituted N-heteroarene-2-carboxamides has been developed for the synthesis of secondary imides. The reaction tolerates various functionalities, such as methoxy, fluoro, chloro, and bromo groups. A tentative radical mechanism for a PdII/PdIV catalytic cycle is proposed. Copyright

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EPOXYKETONE COMPOUNDS FOR ENZYME INHIBITION

The present disclosure relates to novel compounds and pharmaceutical compositions thereof which are useful as inhibitors of proteasomes. The compounds provided herein have improved proteasome potency and selectivity, and increased aqueous solubility, and are useful in treating various conditions or diseases associated with proteasomes.

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Structure?activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors

A series of peptidomimetic aldehydes were designed, synthesized, and evaluated for their biochemical activity against 3C protease (3Cpro) and anti-enterovirus 71 (EV71) activity in?vitro. Molecular docking revealed that 5s (IC50?=?0.22?¡À?0.07?muM, EC50?=?0.18?¡À?0.05?muM) could bind well to the active site of EV71 3Cpro, which was consistent with the biological data compared to reference 5a (IC50?=?0.54?¡À?0.02?muM, EC50?=?0.26?¡À?0.07?muM). Structure and relationship study led to the discovery of aldehyde 5x (IC50?=?0.10?¡À?0.02?muM, EC50?=?0.11?¡À?0.07?muM), which exhibited the most potent 3Cproinhibitory and antiviral activity.

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Compounds for enzyme inhibition

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases associated with the proteasome. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation. Oral administration of these peptide-based proteasome inhibitors is possible due to their bioavailability profiles

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Certain triazole compounds and their pharmaceutical uses

In the invention of novel nonsteroidal antiinflammatory compounds the title novel triazole compounds, were synthesized from carboxylic acids, 2,5-acetonylacetone, or isoniazid, respectively. To give 4H-1,2,4-triazol-3-thiols. Treatment of 4H-1,2,4-tri-azol-3-thiols with methyl chloroacetate or methyl alpha-chloropropionate resulted in the formation of compounds I-VI. The antiinflammatory activity of those new triazole compounds were determined by the carrageenin-induced edema method and they showed potent activity. In the dosage form studies those compounds of formula I-VI were added suituble vehicleo to prepare antiinflammatory agents.

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Synthesis of Novel 3-(3-(5-Methylisoxazol-3-yl)-7H-[1,2,4]Triazolo [3,4-b][1,3,4]Thiadiazin-6-yl)-2H-Chromen-2-Ones

(Chemical Equation Presented) A novel series of coumarin substituted triazolo-thiadiazine derivatives were designed and synthesized by using 5-methyl isoxazole-3-carboxylic acid (1), thiocarbohydrazide (2), and various substituted 3-(2-bromo acetyl) coumarins (4a, 4b, 4c, 4e, 4d, 4f, 4g, 4h, 4i, 4j). Fusion of 5-methyl isoxazole-3-carboxylic acid with thiocarbohydrazide resulted in the formation of the intermediate 4-amino-5-(5-methylisoxazol-3-yl)-4H-1,2,4-triazole-3-thiol (3). This intermediate on further reaction with substituted 3-(2-bromo acetyl) coumarins under simple reaction conditions formed the title products 3-(3-(5-methylisoxazol-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl-2H-chromen-2-ones (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j) in good to excellent yields. All the synthesized compounds were well characterized by physical, analytical, and spectroscopic techniques.

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Isoxazole derivatives and methods of treating nitric oxide mediated diseases

A series of isoxazole derivatives and methods of suppressing, inhibiting, or preventing disorders mediated by nitric oxide (NO) and/or proinflammatory cytokines, such as TNF-alpha (tumor necrosis factor alpha), IL-1 (interlukin-1), and IL-6, are described.

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Imidazo[4,5-d]thiazolo[5,4-b]pyridine based inhibitors of IKK2: Synthesis, SAR, PK/PD and activity in a preclinical model of rheumatoid arthritis

The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.

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Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases

Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CLpro) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL pro of severe-acute-respiratory-syndrome-coronavirus. The IC 50 values of the inhibitors were in the range of 4.6-49 muM, demonstrating that the nitrile warhead can effectively inactivate the 3CL pro autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ?10x more potent than the other inhibitors tested. Crystal structures of the enzyme-inhibitor complexes showed that the nitrile warhead inhibits 3CLpro by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CLpro from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC 50 values ranging from 1.3 to 3.7 muM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CLpro, and they inhibit 3CLpro from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection.

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