Heterocyclic Building Blocks-Benzothiophene

Mancy, Annah published the artcileInteraction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9, Product Details of C13H8Cl2O4S, the main research area is cytochrome P450 sulfaphenazole substrate binding site.

The effects of sulfaphenazole (I) on typical activities catalyzed by human cytochromes P 450 of the 1A, 3A, and 2C subfamilies expressed in yeast were studied. I acts as a strong, competitive inhibitor of CYP 2C9 (Ki = 0.3 ± 0.1 μM); it is much less potent toward CYP 2C8 and 2C18 (Ki = 63 and 29 μM, resp.) and fails to inhibit CYP 1A1, 1A2, 3A4, and 2C19. From difference visible spectroscopy experiments using microsomes of yeast expressing various human P450s, I selectively interacts only with CYP 2C9 with the appearance of a peak at 429 nm as expected for the formation of a P 450 Fe(III)-nitrogenous ligand complex (Ks = 0.4 ± 0.1 μM). Comparative studies of the spectral interaction and inhibitory effects of twelve compounds related to I with CYP 2C9 showed that the aniline function of I is responsible for the formation of the iron-nitrogen bond of the 429 nm-absorbing complex and is necessary for the inhibitory effects of I. The study of two new compounds synthesized during this work, in which the N-Ph group of I was replaced with either an Et group or a 3,4-dichlorophenyl group, showed that the presence of an hydrophobic substituent at position I of the pyrazole function of I is required for a strong interaction with CYP 2C9. A model for the binding of I in the CYP 2C9 active site is proposed; that takes into account three major interactions that should be at the origin of the high-affinity and specific inhibitory effects of I toward CYP 2C9: (i) the binding of its nitrogen atom to CYP 2C9 iron, (ii) an ionic interaction of its SO2N- anionic site with a cationic residue of CYP 2C9, and (iii) an interaction of its N-Ph group with an hydrophobic part of the protein active site.

Biochemistry published new progress about Enzyme functional sites. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Freitas, R. F. published the artcileNovel Application of 2D and 3D-Similarity Searches To Identify Substrates among Cytochrome P450 2C9, 2D6, and 3A4, Product Details of C13H8Cl2O4S, the main research area is similarity search cytochrome P 450 2C9 2D6 3A4 substrate.

Cytochrome P 450 (CYP450) is a class of enzymes where the substrate identification is particularly important to know. It would help medicinal chemists to design drugs with lower side effects due to drug-drug interactions and to extensive genetic polymorphism. Herein, the application of the 2D and 3D-similarity searches in identifying reference structures with higher capacity to retrieve substrates of three important CYP enzymes (CYP2C9, CYP2D6, and CYP3A4) is discussed. On the basis of the complementarities of multiple reference structures selected by different similarity search methods, it is proposed that their individual Tanimoto scores be fused into a consensus Tanimoto score (Tconsensus). Using this new score, true pos. rates of 63% (CYP2C9) and 81% (CYP2D6) were achieved with false pos. rates of 4% for the CYP2C9-CYP2D6 data set. Extended similarity searches were carried out on a validation data set, and the results showed that by using the Tconsensus score, not only the area of a ROC graph increased, but also more substrates were recovered at the beginning of a ranked list.

Journal of Chemical Information and Modeling published new progress about Drug screening, virtual. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Mori, K. published the artcileCocktail-substrate assay system for mechanism-based inhibition of CYP2C9, CYP2D6, and CYP3A using human liver microsomes at an early stage of drug development, Synthetic Route of 40180-04-9, the main research area is cocktail substrate assay cytochrome P450 liver microsome drug development.

1. We established a mechanism-based inhibition cocktail-substrate assay system using human liver microsomes and drugprobe substrates that enabled simultaneous estimation of the inactivation of main cytochrome P 450 (CYP) enzymes, CYP2C9, CYP2D6, and CYP3A, in drug metabolism 2. The inactivation kinetic parameters of typical mechanism-based inhibitors, tienilic acid, paroxetine, and erythromycin, for each enzyme in the cocktail-substrate assay were almost in agreement with the values obtained in the single-substrate assay. 3. Using this system, we confirmed that multiple CYP inactivation caused by mechanism-based inhibitors such as isoniazid and amiodarone could be detected simultaneously. 4. Mechanism-based inhibition potency can be estimated by the determination of the observed inactivation rate constants (kobs) at a single concentration of test compounds because the kobs of eleven CYP3A inactivators at 10×M in the assay system nearly corresponded to kinact/KI values, an indicator of a compound’s propensity to alter the activity of a CYP in vivo (R2 = 0.97). 5 Therefore, this cocktail-substrate assay is considered to be a powerful tool for evaluating mechanism-based inhibition at an early stage of drug development.

Xenobiotica published new progress about Combination chemotherapy. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Synthetic Route of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Harsha, Kachigere b. published the artcileA green synthesis of 1,5-benzodiazepines using reusable-heterogeneous silica sulfuric acid catalyst under solvent-free conditions and their antileukemic activity, Application In Synthesis of 1468-83-3, the main research area is benzodiazepines silica sulfuric acid catalyst antileukemic activity green synthesis.

1,5-Benzodiazepine derivatives are readily assembled from o-phenylene diamine and ketones containg α-hydrogen atoms by means of simple cyclocondensation via sp3 C-H activation promoted by an efficient heterogeneous silica sulfuric acid catalyst. Eco-friendliness, good yields, easy workup, reusable catalyst, short reaction times, high atom economy and solvent-free conditions are the noteworthy features of this protocol. These benzodiazepines are chosen for the evaluation of antiproliferative activity against different leukemia cell lines. Among the investigated compounds, 3g is the best antiproliferative agent against all the cell lines tested. Also, current preliminary anal. showed that compound 3g phosphorylates ERK1/2 and induces G1 arrest in K562 cells.

Asian Journal of Chemistry published new progress about Antiproliferative agents. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Application In Synthesis of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Verbitskiy, Egor V. published the artcileSynthesis, and structure-activity relationship for C(4) and/or C(5) thienyl substituted pyrimidines, as a new family of antimycobacterial compounds, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is thienyl pyrimidine preparation antimycobacterial agent crystal structure; Antimicobacterial; Cross-coupling; Nucleophilic aromatic substitution of hydrogen; Pyrimidine; Tuberculosis.

Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SHN) reactions proved to be a convenient method for the synthesis of C(4) and/or C(5) mono(thienyl) and di(thienyl) substituted pyrimidines from com. available 5-bromopyrimidine. All new pyrimidines are active in micromolar concentrations in vitro against H37Rv, avium, terrae, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The data for acute in vivo toxicity in mice were obtained for these compounds which appear to be promising antitubercular agents.

European Journal of Medicinal Chemistry published new progress about Antimycobacterial agents. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Masubuchi, Yasuhiro published the artcileToxicological significance of mechanism-based inactivation of cytochrome P450 enzymes by drugs, Category: benzothiophene, the main research area is review cytochrome terfenadine astemizole griseofulvin tienilic acid dihydralazine.

Cytochrome P 450 (P 450) enzymes oxidize xenobiotics into chem. reactive metabolites or intermediates as well as into stable metabolites. If the reactivity of the product is very high, it binds to a catalytic site or sites of the enzyme itself and inactivates it. This phenomenon is referred to as mechanism-based inactivation. Many clin. important drugs are mechanism-based inactivators that include macrolide antibiotics, calcium channel blockers, and selective serotonin uptake inhibitors, but are not always structurally and pharmacol. related. The inactivation of P450s during drug therapy results in serious drug interactions, since irreversibility of the binding allows enzyme inhibition to be prolonged after elimination of the causal drug. The inhibition of the metabolism of drugs with narrow therapeutic indexes, such as terfenadine and astemizole, leads to toxicities. On the other hand, the fate of P450s after the inactivation and the toxicol. consequences remains to be elucidated, while it has been suggested that P450s modified and degraded are involved in some forms of tissue toxicity. Porphyrinogenic drugs, such as griseofulvin, cause mechanism-based heme inactivation, leading to formation of ferrochelatase-inhibitory N-alkylated protoporphyrins and resulting in porphyria. Involvement of P 450-derived free heme in halothane-induced hepatotoxicity and catalytic iron in cisplatin-induced nephrotoxicity has also been suggested. Autoantibodies against P450s have been found in hepatitis following administration of tienilic acid and dihydralazine. Tienilic acid is activated by and covalently bound to CYP2C9, and the neoantigens thus formed activate immune systems, resulting in the formation of an autoantibody directed against CYP2C9, named anti-liver/kidney microsomal autoantibody type 2, whereas the pathol. role of the autoantibodies in drug-induced hepatitis remains largely unknown.

Critical Reviews in Toxicology published new progress about 5-HT reuptake inhibitors. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Zhuang, Shi-Yi published the artcileI2-DMSO Mediated N-H/α-C(sp3)-H Difunctionalization of Tetrahydroisoquinoline: Formal [2 + 2 + 1] Annulation for the Construction of Pyrrolo[2,1-a]isoquinoline Derivatives, SDS of cas: 1468-83-3, the main research area is pyrroloisoquinoline preparation; methyl ketone tetrahydroisoquinoline cascade formal cyclization iodine dimethyl sulfoxide.

An I2-DMSO mediated cascade reaction using Me ketones and 1,2,3,4-tetrahydroisoquinolines (THIQs) as com. available substrates has been developed for construction of pyrrolo[2,1-a]isoquinoline derivatives This metal-free process involves N-H/α-C(sp3)-H difunctionalization of THIQ. Two C-C bonds and one C-N bond are formed in one pot under mild conditions. Besides, a quaternary carbon center has been constructed in this transformation efficiently.

Organic Letters published new progress about Cyclization ([2 + 2 + 1]). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, SDS of cas: 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Biagini, Christine P. published the artcileInvestigation of the hepatotoxicity profile of chemical entities using Liverbeads and WIF-B9 in vitro models, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is hepatotoxicity chem Liverbeads WIFB9 bioassay.

The cytotoxicity profile of various chem. entities was evaluated using 2 in vitro hepatocyte models. Liverbeads is a cryopreserved model consisting of primary hepatocytes entrapped in alginate beads. WIF-B9 is a hybrid cell line obtained by fusion of rat hepatoma (Fao) and human fibroblasts (WI38). Various reference hepatotoxicants were tested and ranked according to their equivalent concentration 50 (EC50) for various biochem. endpoints (lactate dehydrogenase (LDH) release, 3-(4,5 dimethylthiazol 2yl)-2,5-diphenyl-2H tetrazolium bromure (MTT) activity, ATP (ATP) and glutathione (GSH) levels). The ranking obtained was comparable in both models and consistent with previously published results on hepatocyte monolayers. Ketoconazole, erythromycin estolate, retinoic acid, telithromycin and α-naphthyl-isothiocyanate were among the most toxic chems. in both models, with an EC50 < 200 μM. Troleandomycin, spiramycin, erythromycin, diclofenac, taurodeoxycholate, warfarin, galactosamine, valproic acid and isoniazid were found to be less toxic. Few marked differences, potentially linked to metabolism pathways, were observed between EC50s in the two models for compounds such as cyclosporine A (10 and >831 μM) and warfarin (5904 and 1489 μM) in WIF-B9 and Liverbeads, resp. The results obtained indicate that Liverbeads and WIF-B9 cells are reliable in vitro models to evaluate the hepatotoxic potential of a wide range of chems., irresp. of structure and pharmaceutical class.

Toxicology in Vitro published new progress about Animal cell line (WIF-B9). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Food and Drug Administration, HHS published the artcileList of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness, SDS of cas: 40180-04-9, the main research area is drug safety effectiveness standard.

The Food and Drug Administration (FDA) is amending its regulations to include a list of drug products that may not be used for pharmacy compounding under the exemptions under section 503A of the Federal Food, Drug, and Cosmetic Act because they have had their approval withdrawn or were removed from the market because the drug product or its components have been found to be unsafe or not effective. The list has been compiled under the new statutory requirements of the Food and Drug Administration Modernization Act of 1997 (Modernization Act).

Federal Register published new progress about Adrenal cortex (extracts). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, SDS of cas: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Ha-Duong, Nguyet-Thanh published the artcileTiclopidine as a Selective Mechanism-Based Inhibitor of Human Cytochrome P450 2C19, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is ticlopidine inhibition cytochrome P450 2C19.

Experiments using recombinant yeast-expressed human liver cytochromes P 450 confirmed previous literature data indicating that ticlopidine is an inhibitor of CYP 2C19. The present studies demonstrated that ticlopidine is selective for CYP 2C19 within the CYP 2C subfamily. UV-visible studies on the interaction of a series of ticlopidine derivatives with CYP 2C19 showed that ticlopidine binds to the CYP 2C19 active site with a Ks value of 2.8 ± 1 μM. Derivatives that do not involve either the o-chlorophenyl substituent, the free tertiary amine function, or the thiophene ring of ticlopidine did not lead to such spectral interactions and failed to inhibit CYP 2C19. Ticlopidine is oxidized by CYP 2C19 with formation of two major metabolites, the keto tautomer of 2-hydroxyticlopidine (1) and the dimers of ticlopidine S-oxide (TSOD) (Vmax = 13 ± 2 and 0.4 ± 0.1 min-1). During this oxidation, CYP 2C19 was inactivated; the rate of its inactivation was time and ticlopidine concentration dependent. This process meets the chem. and kinetic criteria generally accepted for mechanism-based enzyme inactivation. It occurs in parallel with CYP 2C19-catalyzed oxidation of ticlopidine, is inhibited by an alternative well-known substrate of CYP 2C19, omeprazole, and correlates with the covalent binding of ticlopidine metabolite(s) to proteins. Moreover, CYP 2C19 inactivation is not inhibited by the presence of 5 mM glutathione, suggesting that it is due to an alkylation occurring inside the CYP 2C19 active site. The effects of ticlopidine on CYP 2C19 are very analogous with those previously described for the inactivation of CYP 2C9 by tienilic acid. This suggests that a similar electrophilic intermediate, possibly a thiophene S-oxide, is involved in the inactivation of CYP 2C19 and CYP 2C9 by ticlopidine and tienilic acid, resp. The kinetic parameters calculated for ticlopidine-dependent inactivation of CYP 2C19, i.e., t1/2max = 3.4 min, kinact = 3.2 10-3 s-1, KI = 87 μM, kinact/KI = 37 L·mol-1·s-1, and r (partition ratio) = 26 (in relation with formation of 1 + TSOD), classify ticlopidine as an efficient mechanism-based inhibitor although somewhat less efficient than tienilic acid for CYP 2C9. Importantly, ticlopidine is the first selective mechanism-based inhibitor of human liver CYP 2C19 and should be a new interesting tool for studying the topol. of the active site of CYP 2C19.

Biochemistry published new progress about Enzyme inhibition kinetics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem