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PubMed Journals Articles About "Bicyclic Heteroaryl Derivatives Inhibitors Synuclein Protein Patent Evaluation" RSS

06:29 EDT 21st March 2019 | BioPortfolio

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Showing "Bicyclic heteroaryl derivatives inhibitors synuclein protein patent evaluation" PubMed Articles 1–25 of 27,000+

Bicyclic bis-heteroaryl derivatives as inhibitors of the α-synuclein protein: a patent evaluation of WO2018138088A1.

Neurodegenerative diseases commonly present misfolding and aggregation of one or more proteins, including α-synuclein, β-amyloid and tau. Several research efforts have been made to develop therapeutic agents able to reduce the neurotoxic effects of aggregated proteins. Among these, the inhibition of α-synuclein by small molecules has been considered a promising approach. Areas covered: New bis-heteroaryl derivatives based on the N-[1-(1H-indol-3-yl)hexan-2-yl]-1,3-thiazole-5-carboxamide scaffold with dif...


Specific interactions between 2-trans enoyl-acyl carrier protein reductase and its ligand: Protein-ligand docking and ab initio fragment molecular orbital calculations.

2-trans enoyl-acyl carrier protein reductase (InhA) has been identified as a promising target for the development of novel chemotherapy for tuberculosis. In the present study, a series of heteroaryl benzamide derivatives were selected as potent inhibitors against InhA, and their binding properties with InhA were investigated at atomic and electronic levels by ab initio molecular simulations based on protein-ligand docking, classical molecular mechanics optimizations and ab initio fragment molecular orbital ...

Design, Synthesis and Evaluation of Novel Heteroaryldihydropyrimidines Derivatives as Non-nucleoside Hepatitis B Virus Inhibitors by Exploring the Solvent-exposed Region.

In continuation of our efforts toward the discovery of potent non-nucleoside HBV inhibitors with novel structures, we have explored the solvent-exposed protein region of heteroaryldihydropyrimidines (HAPs) derivatives. Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non-nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti-HBV DNA replication activity compared to lamivudine. In ...


Comparative Molecular Field Analysis and Molecular Docking Studies on Quinolinone Derivatives Indicate Potential Hepatitis C Virus Inhibitors.

Presently, there are no effective vaccines and anti-virals for the prevention and treatment of Hepatitis C virus infections and hence there is an urgent need to develop potent HCV inhibitors. In this study, we have carried out molecular docking, molecular dynamics and 3D-QSAR on heteroaryl 3-(1,1-dioxo-2H-(1,2,4)-benzothiadizin-3-yl)-4-hydroxy-2(1H)-quinolinone series using NS5B protein. Total of 41 quinolinone derivatives is used for molecular modeling study. The binding conformation and hydrogen bond inte...

Synthesis and evaluation of novel GSK-3β inhibitors as multifunctional agents against Alzheimer's disease.

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu, Zn and Al chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3β inhibitors and selective Cuand Al chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3β inhibitory potency. In vitro, compo...

Iron-induced oxidative stress contributes to α-synuclein phosphorylation and up-regulation via polo-like kinase 2 and casein kinase 2.

α-Synuclein plays a central role in synucleinopathies pathogenesis such as Parkinson's disease (PD). Phosphorylation is the most common and important protein modification linked to α-synuclein pathologies. There is mounting evidence suggested iron and α-synuclein are closely related in PD. We previously reported iron up-regulated α-synuclein mRNA levels and induced α-synuclein aggregation. In the present study, we aimed to investigate whether and how phosphorylation was involved in iron-induced α-synu...

Design, synthesis and biological evaluation of 2-nitroimidazopyrazin-one/-es with antitubercular and antiparasitic activity.

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that anti-tubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidaz...

Lead optimization and biological evaluation of fragment-based cN-II inhibitors.

The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused libr...

C-Phycocyanin from Spirulina Inhibits α-Synuclein and Amyloid-β Fibril Formation but Not Amorphous Aggregation.

Proteinopathies including cataracts and neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are characterized by a series of aberrant protein folding events, resulting in amorphous aggregate or amyloid fibril formation. In the latter case, research has heavily focused on the development of small-molecule inhibitors with limited success during clinical trials. However, very few studies have focused on utilizing exogenous proteins as potential aggregation inhibitors. C-Phycocyanin, derive...

Toward the discovery and development of effective modulators of α-synuclein amyloid aggregation.

A host of human diseases, including Parkinson's disease and Dementia with Lewy bodies, are suspected to be directly linked to protein aggregation. Amyloid protein aggregates and oligomeric intermediates of α-synuclein are observed in synucleinopathies and considered to be mediators of cellular toxicity. Hence, α-synuclein has seen as one of the leading and most compelling targets and is receiving a great deal of attention from researchers. Nevertheless, there is no neuroprotective approach directed toward...

Membrane-Protein-Hydration Interaction of α-Synuclein with Anionic Vesicles Probed via Angle-Resolved Second Harmonic Scattering.

Amyloid formation of the protein α-synuclein promotes neurodegeneration in Parkinson's disease. The normal function of α-synuclein includes synaptic vesicle transport and fusion, and the protein binds strongly to negatively charged vesicles in vitro. Here we demonstrate that non-resonant angle-resolved second harmonic scattering detects α-synuclein binding to liposomes through changes in water orientational correlations and can thus be used as high accuracy and high throughput label-free probe of protein...

Acute inflammation downregulates alpha-synuclein expression in enteric neurons.

The protein alpha-synuclein whose expression is strongly implicated in Parkinson's disease (PD) is not only expressed in the central nervous system (CNS) but also in the enteric nervous system (ENS). The growing body of evidence suggesting that gastrointestinal inflammation is involved in the development of PD led us to investigate the effects of inflammation on alpha-synuclein expression in primary culture of rat ENS and in mice with dextran sulfate sodium (DSS)-induced colitis. Using western blot and qPCR...

Synthesis and evaluation of 2-azetidinone and 1H-pyrrole-2,5-dione derivatives as cholesterol absorption inhibitors for reducing inflammation response and oxidative stress.

Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid-lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2-azetidinone derivatives and eighteen 1H-pyrrole-2,5-dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake in vitro. In addition, one...

Thiourea dioxide as a source of sulfonyl groups: photoredox generation of sulfones and sulfonamides from heteroaryl/aryl halides.

Thiourea dioxide as the source of sulfonyl groups for the efficient synthesis of heteroaryl sulfones and sulfonamides from heteroaryl halides under visible light irradiation is reported. This transformation proceeds smoothly via heteroaryl sulfinate intermediates, which can be trapped in situ by various electrophiles. A broad reaction scope is demonstrated, especially for the electron-deficient heteroaryl halides. Mechanistic studies show that the radical coupling of the heteroaryl radical and sulfur dioxid...

The Cell-Death-Associated Polymer PAR Feeds Forward α-Synuclein Toxicity in Parkinson's Disease.

Parkinson's disease (PD) is characterized by protein aggregates of α-synuclein in neurons. In a recent issue of Science, Kam et al. (2018) revealed a feedforward loop in which α-synuclein increases the levels of poly(adenosine 5'-diphosphate-ribose) (PAR) that in turn causes α-synuclein aggregates to be more toxic. This study advances our understanding of PD pathology.

Identification of β-synuclein on secretory granules in chromaffin cells and the effects of α- and β-synuclein on post-fusion BDNF discharge and fusion pore expansion.

α-Synuclein is strongly implicated in the pathogenesis of Parkinson's disease as well as in other neurodegenerative diseases. However, its normal function in cells is not understood. The N-termini of α-, β-, and γ-synuclein contains six to seven 11-amino acid repeats that are predicted to form amphipathic helices. Membrane-binding and membrane-curving abilities of synuclein raise the possibility that synuclein could alter cellular processes that involve highly curved structures. In the present study we ...

Flurbiprofen derivatives as novel α-amylase inhibitors: Biology-oriented drug synthesis (BIODS), in vitro, and in silico evaluation.

Novel derivatives of flurbiprofen 1-18 including flurbiprofen hydrazide 1, substituted aroyl hydrazides 2-9, 2-mercapto oxadiazole derivative 10, phenacyl substituted 2-mercapto oxadiazole derivatives 11-15, and benzyl substituted 2-mercapto oxadiazole derivatives 16-18 were synthesized and characterized by EI-MS, H and C NMR spectroscopic techniques. All derivatives 1-18 were screened for α-amylase inhibitory activity and demonstrated a varying degree of potential ranging from IC = 1.04 ± 0.3 to ...

The monoamine oxidase inhibition properties of C6-mono- and N3/C6-disubstituted derivatives of 4(3H)-quinazolinone.

Parkinson's disease is characterised by the death of the nigrostriatal neurons and depletion of striatal dopamine. The standard symptomatic therapy consists of dopamine replacement with l-dopa, the metabolic precursor of dopamine, which represents the most effective treatment. Since monoamine oxidase (MAO) B is a key dopamine metabolising enzyme in the brain, MAO-B inhibitors are often used as adjuvants to l-dopa. In addition to the symptomatic benefits offered by MAO-B inhibitors, these drugs may also poss...

Visible-Light-Promoted Transition-Metal-Free Phosphinylation of Heteroaryl Halides in the Presence of Potassium tert-Butoxide.

A novel visible-light-promoted C-P bond formation reaction in the absence of both transition metal and photoredox catalysts is disclosed. By employing easily available and inexpensive heteroaryl chlorides/bromides as substrates, a variety of heteroaryl phosphine oxides were obtained in moderate to good yields. This strategy provides a simple and efficient route to heteroaryl phosphine oxides.

Cellular prion protein neither binds to alpha-synuclein oligomers nor mediates their detrimental effects.

α-Synuclein oligomers are crucial players in the pathogenesis of Parkinson's disease. Some mechanisms involved in α-synuclein oligomer detrimental effects include membrane damage, neuroinflammation and protein-protein interactions. Recently, the cellular prion protein (PrPC) emerged as an interactor of α-synuclein oligomers, apparently mediating their detrimental activities. Through direct in vivo and in vitro approaches we herein investigated the existence of a direct cross-talk between α-synuclein oli...

Predictive classification models and targets identification for betulin derivatives as Leishmania donovani inhibitors.

Betulin derivatives have been proven effective in vitro against Leishmania donovani amastigotes, which cause visceral leishmaniasis. Identifying the molecular targets and molecular mechanisms underlying their action is a currently an unmet challenge. In the present study, we tackle this problem using computational methods to establish properties essential for activity as well as to screen betulin derivatives against potential targets. Recursive partitioning classification methods were explored to develop pr...

The Unlikely Partnership Between LRRK2 and α-Synuclein in Parkinson's Disease.

Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical non-genetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multi-domain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that ...

Design, Synthesis and Biological Evaluation of 6-Substituted Thieno3,2-dpyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors.

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule targeting agents prompted us to design and to develop single agents which possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3',4',5'-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3',4',5'-trimethoxyanilino)-6-(p-tolyl)thien...

Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors.

A series of substituted pyrazole compounds (1-8 and 9a, b) were synthesized and their structure was characterized by IR, NMR, and Mass analysis. These obtained novel pyrazole derivatives (1-8 and 9a, b) were emerged as effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) and acetylcholinesterase (AChE) enzymes with K values in the range of 1.03 ± 0.23-22.65 ± 5.36 µM for hCA I, 1.82 ± 0.30-27.94 ± 4.74 µM for hCA II, and 48.94 ± 9.63-116.05...

Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.

We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protea...


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