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Innovative therapeutic potential of cannabinoid receptors as targets in alzheimer?s disease and less well-known diseases

The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development,32 stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer?s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist. 32.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Heterocyclic scaffolds for the treatment of Alzheimer?s disease

Background: The treatment and diagnosis of Alzheimer?s Disease (AD) are two of the most urgent goals for research around the world. The cognitive decline is generally associated with the elevated levels of extracellular senile plaques, intracellular neurofibrillary tangles (NFTs), and with a progressive shutdown of the cholinergic basal forebrain neurons transmission. Even if several key targets are under fervent investigation in the cure of AD, till now, the only approved therapeutic strategy is the treatment of symptoms by using cholinesterases inhibitors. It has been demonstrated that both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes are not only responsible of acetylcholine levels, but also play an pivotal role in A[1]-aggregation during the early stages of senile plaque formation. On the other hand the difficult management of AD is also related to effective diagnostic methods and efficient assays for the study of pathological features. In such complex a wide framework, heterocyclic molecules are essential backbone to build new and selective drugs as well as diagnostic probes. Methods: The goal of this review is to examine a selected sample of relevant applications of five- and six-membered heterocycles in AD’s therapeutic approaches. Results: Concerning the research on AD, the contribution of heterocyclic compounds is huge and here we report some representative examples. The review is organized in two main sections focused on five and six-membered heterocycles. The analyzed cases have been classified on the base of the structural features of molecules, taking into account the progressive increase in heteroatoms number. Conclusion: The discovery of an effective therapy or a diagnostic protocol for AD is still far, but consistent improvements are underway and contribution of heterocyclic compounds will be consistent and hopefully determinant.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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A vascular endothelial growth factor inhibitors of the oral pharmaceutical composition (by machine translation)

The invention belongs to the field of medicine, in particular to inhibit VEGF salts of the compound of formula I oral pharmaceutical composition, the pharmaceutical use and pharmaceutical formulations, particularly with respect to the tumor, the treatment of angiogenesis. The invention also relates to the method for synthesizing the compounds. (by machine translation)

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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An approximate absolute 33S nuclear magnetic shielding scale

Sulfur-33 chemical shifts have been measured for a number of simple compounds, e.g.SF6, HFSO3, X2SO2, SO2, Cl2SO, CH3SH, H2S, and OCS, which have not been previously reported.Our results indicate that the range of 33S chemical shifts is approximately 1000 ppm, slightly less than that observed for 17O and approximately one half the range reported for 77Se.Using the 33S nuclear spin-rotation constant of OCS measured by molecular-beam electric resonance and Flygare’s procedure, an absolute 33S shielding constant of 843+/-12 ppm is calculated for OCS, permitting an approximate absolute shielding scale to be proposed for this nucleus.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Benzo-fused cyclic compounds

Herbicidal benzo-fused cyclic compounds of the formula STR1 wherein Q is STR2 Y is O or S, W is STR3 T is O, S, –NH– or STR4 and R4 may represent, together with T, chlorine, Z is O or S, X is hydrogen or halogen, n is 0 or 1 and R is C3-6 cycloalkyl, an optionally substituted 5-membered heterocyclic group or an optionally substituted 6-membered heteroaromatic group which contains one to three nitrogen atoms, and salts thereof.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Combinatorial design and virtual screening of potent anti-tubercular fluoroquinolone and isothiazoloquinolone compounds utilizing QSAR and pharmacophore modelling$

The virulence of tuberculosis infections resistant to conventional combination drug regimens cries for the design of potent fluoroquinolone compounds to be used as second line antimycobacterial chemotherapeutics. One of the most effective in silico methods is combinatorial design and high throughput screening by a ligand-based pharmacophore prior to experiment. The combinatorial design of a series of 3850 fluoroquinolone and isothiazoloquinolone compounds was then screened virtually by applying a topological descriptor based quantitative structure activity relationship (QSAR) for predicting highly active congeneric quinolone leads against Mycobacterium fortuitum and Mycobacterium smegmatis. The predicted highly active congeneric hits were then subjected to a comparative study between existing lead sparfloxacin with fluoroquinolone FQ hits as well as ACH-702 with predicted active isothiazoloquinolones, utilizing pharmacophore modelling to focus on the mechanism of drug binding against mycobacterial DNA gyrase. Finally, 68 compounds including 34 FQ and 34 isothiazoloquinolones were screened through high throughput screening comprising QSAR, the Lipinski rule of five and ligand-based pharmacophore modelling.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism

Acetylation, a key component in post-translational modification regulated by HATs and HDACs, is relevant to many crucial cellular contexts in organisms. Based on crucial pharmacophore patterns and the structure of targeted proteins, HAT inhibitors are designed and modified for higher affinity and better bioactivity. However, there are still some challenges, such as cell permeability, selectivity, toxicity and synthetic availability, which limit the improvement of HAT inhibitors. So far, only few HAT inhibitors have been approved for commercialization, indicating the urgent need for more successful and effective structure-based drug design and synthetic strategies. Here, we summarized three classes of HAT inhibitors based on their sources and structural scaffolds, emphasizing on their synthetic methods and structure?activity relationships and molecular mechanisms, hoping to facilitate the development and further application of HAT inhibitors.

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Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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A method for inhibiting VEGF injection of the pharmaceutical composition (by machine translation)

The invention belongs to the field of medicine, in particular to inhibit VEGF of the formula I compound and salt of injection drug composition, in pharmaceutical use and pharmaceutical formulations, particularly with respect to the tumor, the treatment of angiogenesis. The invention also relates to the method for synthesizing the compounds. (by machine translation)

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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Synthesis and investigations of the absorption spectra of hetarylazo disperse dyes derived from 2,4-quinolinediol

Synthesis of some novel hetarylazoquinoline dyes was achieved by diazotisation of nine heterocyclic amines using nitrosyl sulphuric acid, coupling with 2,4-quinolinediol. These dyes were characterized by UV-vis, FT-IR and 1H NMR spectroscopic techniques and elemental analysis. Visible absorption spectra of the dyes are discussed, both the effects of varying pH and solvent upon the absorption ability of azoquinolines. The colour of the dyes was discussed with respect to the nature of the heterocyclic ring and to the substituents therein. Temperature and concentration effects on the visible absorption maxima of the dyes are also reported.

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com

 

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A compound for inhibiting VEGF (by machine translation)

A compound for inhibiting VEGF, the invention belongs to the field of medicine, the special formula I compound and salt. The invention also relates to the method for synthesizing the compounds, in pharmaceutical use and pharmaceutical formulations, particularly with respect to the tumor, the treatment of angiogenesis. (by machine translation)

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Reference£º
Isothiazole – Wikipedia,
Isothiazole – ScienceDirect.com