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ALKYNYL ALCOHOLS AS KINASE INHIBITORS

Selected compounds are effective for prophylaxis and treatment of inflammation and inflammatory disorders, such as NIK-mediated disorders. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, inflammation and the like.

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The position of the N atom in the pentacyclic ring of heterocyclic molecules affects the excited-state decay: A case study of isothiazole and thiazole

The radiationless decay of the isothiazole and thiazole molecules in the gas phase is investigated by a combination of static MS-CASPT2 computations with dynamics simulations, and some deactivation pathways are identified leading from the lowest excited singlet (S1) state back to the electronic ground (S0) state. The dominant relaxation pathway of the excited isothiazole is found to involve out-of-plane ring deformation (ring puckering) at the C4=C5(H8)?S1 moiety, while the excited-state decay of thiazole can proceed through the ring puckering and S1?C2 bond cleavage pathways both of which happen at the S1?C2(H6) = N3 moiety. On the basis of the calculation results, we suggest that both ring-puckering and ring-opening routes should play rather important roles in the photophysics and photochemistry of heterocyclic molecules, and the position of the N atom in the heterocyclic ring has an effect on the excited state deactivation.

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SAR of 2,6-diamino-3,5-difluoropyridinyl substituted heterocycles as novel p38 MAP kinase inhibitors

2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED50: 10 mg/kg po b.i.d.) and collagen induced arthritis (ED50: 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: A Viagra with a pop

A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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A new size-expanded RNA alphabet: Computational design of benzo-homologated (xtz-) isothiazole RNA and comparisons to the x-thieno RNA

Fluorescent nucleobase analogs are of great interest because of their widespread applications in nucleic acids research. In the present work, a new benzo-homologated RNA alphabet comprising xtzA, xtzG, xtzC, and xtzU was computationally designed based on the isomorphic tz-bases. The structural, electronic, and photophysical properties are studied by means of DFT and TDDFT calculations, and the effects of water solution, ribose, and base pairing on the singlet excited transitions were examined. The results are compared with those for tz-bases and xth-bases. These new base analogs can form stable Watson-Crick base pairs with natural counterparts as tz-bases and xth-bases do. Their ionization potentials and HOMO-LUMO gaps are in the middle of tz-bases and xth-bases: xth-base < xtz-base < tz-base. Furthermore, all xtz-bases are predicted to have smaller IPs and HOMO-LUMO gaps than natural bases and tz-bases, they are suggested to be candidates for applications in nanowire technology. The S1 states for all xtz-bases are revealed to be pipi* dominated by the configuration HOMO ? LUMO. In water solution, compared with tz- or xth-bases, the lowest pipi* states are about 20.06?21.91 kcal/mol red-shifted or 0.92?4.15 kcal/mol blue-shifted, respectively. Linking to ribose has negligible effects on the S1 excitation energies, but it owns a larger impact on the corresponding oscillator strengths. Base pairing and water solution as a whole has very little effects on the S1 transition energies of xtzA and xtzC, but it will red-shift those for xtzG and xtzU by 6.69 and 5.30 kcal/mol, respectively. All xtz-bases are expected to display visible fluorescence with the wavelengths predicted to be 540, 585, 524, and 506 nm for xtzA, xtzG, xtzC and xtzU, respectively, in water solution. Though structurally very similar, the excitation maxima and fluorescence emissions of xtz- and xth-bases show distinct differences, allowing them to be distinguished from each other by their spectroscopic characters Do you like my blog? If you like, you can also browse other articles about this kind. Thanks for taking the time to read the blog about 288-16-4 Reference£º
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Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Cytochrome P450 17A1 (CYP17A1) is an important target in the treatment of prostate cancer because it produces androgens required for tumour growth. The FDA has approved only one CYP17A1 inhibitor, abiraterone, which contains a steroidal scaffold similar to the endogenous CYP17A1 substrates. Abiraterone is structurally similar to the substrates of other cytochrome P450 enzymes involved in steroidogenesis, and interference can pose a liability in terms of side effects. Using non-steroidal scaffolds is expected to enable the design of compounds that interact more selectively with CYP17A1. Therefore, we combined a structure-based virtual screening approach with density functional theory (DFT) calculations to suggest non-steroidal compounds selective for CYP17A1. In vitro assays demonstrated that two such compounds selectively inhibited CYP17A1 17alpha-hydroxylase and 17,20-lyase activities with IC50 values in the nanomolar range, without affinity for the major drug-metabolizing CYP2D6 and CYP3A4 enzymes and CYP21A2, with the latter result confirmed in human H295R cells.

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Amino pyridine derivatives

Novel 4-pyridinamine derivatives having the formula STR1 [where R1 and R2 are aryl or heteroaryl (optionally linked together by a lower alkylene bridge) or one of R1 and R2 is aryl or heteroaryl and the other of R1 and R2 is lower alkyl or ar(lower)alkyl, R3 and R4 are each hydrogen or lower alkyl and n is 0 or 1] and their non-toxic acid addition salts are described. They show CNS activity and may be used as antidepressant drugs. Some also show stimulant activity. Novel intermediates having the formula STR2 are also described.

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Five-Membered Ring Systems: With N and S Atom

This review chapter describes the syntheses and reactions of these 5-membered heterocyclic ring systems containing nitrogen and sulfur (reported during 2018). The importance of these p-rich heterocycles in medicinal chemistry and natural products is also covered.

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Stacking Interactions between 9-Methyladenine and Heterocycles Commonly Found in Pharmaceuticals

Complexes of 9-methyladenine with 46 heterocycles commonly found in drugs were located using dispersion-corrected density functional theory, providing a representative set of 408 unique stacked dimers. The predicted binding enthalpies for each heterocycle span a broad range, highlighting the strong dependence of heterocycle stacking interactions on the relative orientation of the interacting rings. Overall, the presence of NH and carbonyl groups lead to the strongest stacking interactions with 9-methyadenine, and the strength of -stacking interactions is sensitive to the distribution of heteroatoms within the ring as well as the specific tautomer considered. Although molecular dipole moments provide a sound predictor of the strengths and orientations of the 28 monocyclic heterocycles considered, dipole moments for the larger fused heterocycles show very little correlation with the predicted binding enthalpies.

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Isothiazole – Wikipedia,
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Chemistry is the science of change. But why do chemical reactions take place? Why do chemicals react with each other? The answer is in thermodynamics and kinetics.In a document type is Article, the author is Raubenheimer, Helgard G. and a compound is mentioned, SDS of cas: 288-16-4, Isothiazole, introducing its new discovery. SDS of cas: 288-16-4

Preparation and Characterization of the First Isothiazolyl and Isothiazolinylidene Complexes of Gold(I)

Isothiazolyl complexes have been synthesized by the addition of isothiazol-5-yllithium to gold(I) chloride or tetrahydrothiophene(pentafluorophenyl)gold complexes.Protonation or alkylation of these isothiazolyl complexes yielded the corresponding isothiazolinylidene complexes.The mono(isothiazolyl)-aurate and mono(isothiazolinylidene) complexes undergo homoleptic rearrangement.The molecular structure of the mono(isothiazolyl) complex shows a gold-carbon bond length of 2.032(7) Angstroem.

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