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Identification of non-peptidic cysteine reactive fragments as inhibitors of cysteine protease rhodesain

Rhodesain, the major cathepsin L-like cysteine protease in the protozoan Trypanosoma brucei rhodesiense, the causative agent of African sleeping sickness, is a well-validated drug target. In this work, we used a fragment-based approach to identify inhibitors of this cysteine protease, and identified inhibitors of T. brucei. To discover inhibitors active against rhodesain and T. brucei, we screened a library of covalent fragments against rhodesain and conducted preliminary SAR studies. We envision that in vitro enzymatic assays will further expand the use of the covalent tethering method, a simple fragment-based drug discovery technique to discover covalent drug leads.

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Reference£º
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

Brief introduction of Methyl 4-bromobenzo[b]thiophene-2-carboxylate

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Indazole-and indole-5-carboxamides: Selective and reversible monoamine oxidase B inhibitors with subnanomolar potency

Indazole-and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4- dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC 50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4- dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4- difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A >6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors’ interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

Top Picks: new discover of Methyl 4-bromobenzo[b]thiophene-2-carboxylate

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Antiparasitic, anti-inflammatory and cytotoxic activities of 2D coordination polymers based on 1H-indazole-5-carboxylic acid

We report on the formation of two novel multifunctional isomorphous (4,4) square-grid 2D coordination polymers based on 1H-indazole-5-carboxylic acid. To the best of our knowledge, these complexes are the first examples of 2D-coordination polymers constructed with this novel ligand. We have analysed in detail the structural, magnetic and anti-parasitic properties of the resulting materials. In addition, the capability of inhibiting nitric oxide production from macrophage cells has been measured and was used as an indirect measure of the anti-inflammatory response. Finally, the photocatalytic activity was measured with a model pollutant, i.e. vanillic acid (phenolic compound), with the aim of further increasing the functionalities and applicability of the compounds.

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

Brief introduction of Methyl 4-bromobenzo[b]thiophene-2-carboxylate

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In heterogeneous catalysis, the catalyst is in a different phase from the reactants. Computed Properties of C10H7BrO2S, At least one of the reactants interacts with the solid surface in a physical process called adsorption in such a way. 360575-29-7, name is Methyl 4-bromobenzo[b]thiophene-2-carboxylate. In an article£¬Which mentioned a new discovery about 360575-29-7

THIAZOLOPYRIMIDINE COMPOUNDS

The present invention relates to the use of novel pyrrolopyrazine derivatives of formula I: wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

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INDAZOLES, BENZOTHIAZOLES, AND BENZOISOTHIAZOLES, AND PREPARATION AND USES THEREOF

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the alpha7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

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Crystal structures, binding interactions, and ADME evaluation of brain penetrant N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors

The pharmacological and physicochemical analysis of structurally optimized N-alkyl-substituted indazole-5-carboxamides, developed as potential drug and radioligand candidates for the treatment and diagnosis of Parkinson’s disease (PD) and other neurological disorders, is reported. Recent efforts have been focused on the development of subnanomolar potent, selective MAO-B (N1-alkyl-substituted compounds 12a?14a and 15) and dual active MAO-A/B (N2-methylated compounds 12b?14b) inhibitors with nanomolar potency towards MAO-B and moderately active against MAO-A enzyme, respectively. The most promising drug-like derivatives in both series were N-(3-chloro-4-fluorophenyl)-1-methyl-1H-indazole-5-carboxamide (13a, NTZ-1441, IC50hMAO-B 0.662?nM, >15000-fold selective versus MAO-A) and N-(3-chloro-4-fluorophenyl)-2-methyl-2H-indazole-5-carboxamide (13b, NTZ-1442, IC50hMAO-B 8.08?nM, IC50hMAO-A 0.56?muM, SI?=?70). Moreover, compounds 13a and 13b were predicted to cross both the gastrointestinal tract (at pH 2.0, 5.5, and 7,4) and the blood-brain barrier (BBB) in?vitro with appropriate drug-like properties required for CNS active drugs. Combined single X-ray/molecular modeling studies provided insights into the enzyme?inhibitor interactions within both MAO isoforms and the rationale for their inhibitory activity with controlled MAO-A/B selectivity ? despite their small structural differences. The binding modes of 12a,b and 13a,b confirmed that the major interactions with hMAO-B were established via the flexible carbonyl group of the carboxamide linkage and the electron-donating nitrogens N1 or N2 of the indazole moiety, allowing further exploration of the alkyl side chain for next step lead optimization efforts.

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Reference£º
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

Discovery of Methyl 4-bromobenzo[b]thiophene-2-carboxylate

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NOVEL ARYLALKENE DERIVATIVES AND USE THEREOF AS SELECTIVE ESTROGEN RECEPTOR MODULATORS

The invention provides novel ethylene derivatives represented by Formula I, which may be used as selective estrogen receptor modulators (SERMs) and useful in the prophylaxis and/or treatment of estrogen-dependent conditions or conditions.

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

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TRIAZA-SPIRODECANONES AS DDR1 INHIBITORS

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein L and R1 to R5 are as described herein, as well as processes for their manufacture, pharmaceutical compositions comprising them, and their use as medicaments.

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

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N1-PYRAZOLOSPIROKETONE ACETYL-COA CARBOXYLASE INHIBITORS

The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of the compound, wherein R1, R2, R3 and R4 are as described herein; pharmaceutical compositions there-of; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl- CoA carboxylase enzyme(s) in an animal

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Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

 

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Off-DNA DNA-Encoded Library Affinity Screening

DNA-encoded library (DEL) technology is emerging as a key element of the small molecule discovery toolbox. Conventional DEL screens (i.e., on-DNA screening) interrogate large combinatorial libraries via affinity selection of DNA-tagged library members that are ligands of a purified and immobilized protein target. In these selections, the DNA tags can materially and undesirably influence target binding and, therefore, the experiment outcome. Here, we use a solid-phase DEL and droplet-based microfluidic screening to separate the DEL member from its DNA tag (i.e., off-DNA screening), for subsequent in-droplet laser-induced fluorescence polarization (FP) detection of target binding, obviating DNA tag interference. Using the receptor tyrosine kinase (RTK) discoidin domain receptor 1 (DDR1) as a proof-of-concept target in a droplet-scale competition-binding assay, we screened a 67 100-member solid-phase DEL of drug-like small molecules for competitive ligands of DDR1 and identified several known RTK inhibitor pharmacophores, including azaindole- and quinazolinone-containing monomers. Off-DNA DEL affinity screening with FP detection is potentially amenable to a wide array of target classes, including nucleic acid binding proteins, proteins that are difficult to overexpress and purify, or targets with no known activity assay.

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Reference£º
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem