Heterocyclic Building Blocks-Benzothiophene

Contrera, Joseph F. published the artcileEstimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose, Computed Properties of 40180-04-9, the main research area is QSAR structure activity relationship mol modeling drug screening.

Estimating the maximum recommended starting dose (MRSD) of a pharmaceutical for phase I human clin. trials and the no observed effect level (NOEL) for non-pharmaceuticals is currently based exclusively on an extrapolation of the results of animal toxicity studies. This process is inexact and requires the results of toxicity studies in multiple species (rat, dog, and monkey) to identify the no observed adverse effect level (NOAEL) and most sensitive test species. Multiple uncertainty (safety) factors are also necessary to compensate for incompatibility and uncertainty underlying the extrapolation of animal toxicity to humans. The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clin. trials. The MRDD is an estimated upper dose limit beyond which a drug’s efficacy is not increased and/or undesirable adverse effects begin to outweigh beneficial effects. The MRDD is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicol.) or undesirable pharmacol. effects are observed The NOAEL in test animals is currently used to estimate the safe starting dose in human clin. trials. MDL QSAR predictive modeling of the human MRDD may provide a better, simpler and more relevant estimation of the MRSD for pharmaceuticals and the toxic dose threshold of chems. in humans than current animal extrapolation based risk assessment models and may be a useful addition to current methods. A database of the MRDD for over 1300 pharmaceuticals was compiled and modeled using MDL QSAR software and E-state and connectivity topol. descriptors. MDL QSAR MRDD models were found to have good predictive performance with 74-78% of predicted MRDD values for 120 internal and 160 external validation compounds falling within a range of ±10-fold the actual MRDD value. The predicted MRDD can be used to estimate the MRSD for pharmaceuticals in phase I clin. trials with the addition of a 10-fold safety factor. For non-pharmaceutical chems. any compound-related effect can be considered an undesirable and adverse toxicol. effect and the predicted MRDD can be used to estimate the NOEL with the addition of an appropriate safety factor.

Regulatory Toxicology and Pharmacology published new progress about Clinical trials. 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, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Jaladanki, Chaitanya K. published the artcileToxicity Originating from Thiophene Containing Drugs: Exploring the Mechanism using Quantum Chemical Methods, Application In Synthesis of 40180-04-9, the main research area is thiophene drug toxicity quantum chem cytochrome P 450 metabolism.

Drug metabolism of thiophene containing substrates by cytochrome P450s (CYP450) leads to toxic side effects, for example, nephrotoxicity (suprofen, ticlopidine), hepatotoxicity (tienilic acid), thrombotic thrombocytopenic purpura (clopidogrel), and aplastic anemia (ticlopidine). The origin of toxicity in these cases has been attributed to two different CYP450 mediated metabolic reactions: S-oxidation and epoxidation In this work, the mol. level details of the bioinorganic chem. associated with the generation of these competitive reactions are reported. D. functional theory was utilized (i) to explore the mol. mechanism for S-oxidation and epoxidation using the radical cationic center Cpd I [(iron(IV)-oxo-heme porphine system with SH- as the axial ligand, to mimic CYP450s] as the model oxidant, (ii) to establish the 3D structures of the reactants, transition states, and products on both the metabolic pathways, and (iii) to examine the potential energy (PE) profile for both the pathways to determine the energetically preferred toxic metabolite formation. The energy barrier required for S-oxidation was observed to be 14.75 kcal/mol as compared to that of the epoxidation reaction (13.23 kcal/mol) on the doublet PE surface of Cpd I. The formation of the epoxide metabolite was found to be highly exothermic (-23.24 kcal/mol), as compared to S-oxidation (-8.08 kcal/mol). Hence, on a relative scale the epoxidation process was observed to be thermodynamically and kinetically more favorable. The energy profiles associated with the reactions of the S-oxide and epoxide toxic metabolites were also explored. This study helps in understanding the CYP450-catalyzed toxic reactions of drugs containing the thiophene ring at the at. level.

Chemical Research in Toxicology published new progress about Aplastic anemia. 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, Application In Synthesis of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Martin, Parthena published the artcileIn vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions, Product Details of C13H8Cl2O4S, the main research area is liver cell fenfluramine norfenfluramine drug interaction; antiepileptics; cytochrome P450; drug transport; drug-drug interactions.

Fenfluramine (FFA) has potent antiseizure activity in severe, pharmacoresistant childhood-onset developmental and epileptic encephalopathies (e.g., Dravet syndrome). To assess risk of drug interaction affecting pharmacokinetics of FFA and its major metabolite, norfenfluramine (nFFA), we conducted in vitro metabolite characterization, reaction phenotyping, and drug transporter-mediated cellular uptake studies. FFA showed low in vitro clearance in human liver S9 fractions and in intestinal S9 fractions in all three species tested (t1/2 > 120 min). Two metabolites (nFFA and an N-oxide or a hydroxylamine) were detected in human liver microsomes vs. six in dog and seven in rat liver microsomes; no metabolite was unique to humans. Selective CYP inhibitor studies showed FFA metabolism partially inhibited by quinidine (CYP2D6, 48%), phencyclidine (CYP2B6, 42%), and furafylline (CYP1A2, 32%) and, to a lesser extent (<15%), by tienilic acid (CYP2C9), esomeprazole (CYP2C19), and troleandomycin (CYP3A4/5). Incubation of nFFA with rCYP1A2, rCYP2B6, rCYP2C19, and rCYP2D6 resulted in 10%-20% metabolism and no clear inhibition of nFFA metabolism by any CYP-selective inhibitor. Reaction phenotyping showed metabolism of FFA by recombinant human cytochrome P 450 (rCYP) enzymes rCYP2B6 (10%-21% disappearance for 1 and 10μM FFA, resp.), rCYP1A2 (22%-23%), rCYP2C19 (49%-50%), and rCYP2D6 (59%-97%). Neither FFA nor nFFA was a drug transporter substrate. Results show FFA metabolism to nFFA occurs through multiple pathways of elimination. FFA dose adjustments may be needed when administered with strong inhibitors or inducers of multiple enzymes involved in FFA metabolism (e.g., stiripentol). Pharmacology Research & Perspectives published new progress about Anticonvulsants. 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

Pogrebnoi, A. A. published the artcileModeling complexes of substrates with cytochrome P450 2C9, Category: benzothiophene, the main research area is modeling substrate cytochrome P450 2C9 algorithm CiS complex.

Complexes of 16 substrates with 2C9 isoform of Cytochrome P 450 complex taken from the PDB database have been modeled using 3D-QSAR algorithm CiS. The arrangement of substrate mols. and the orientation of their reaction centers with respect to the heme in modeled complexes have been analyzed. The orientation of substrate mols. in the model complexes explains the exptl. observed metabolic reactions. The results show that the CiS algorithm is capable of predicting the metabolic pathways of the modeled complexes.

Pharmaceutical Chemistry Journal published new progress about Algorithm (CiS). 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

Nakayama, Shintaro published the artcileA zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is idiosyncratic drug toxicity daily dose covalent binding risk assessment.

The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. The authors determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression anal. indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression anal. to create three zones, 30 of 37 tested drugs were located in zones corresponding to their resp. classified safety categories. In conclusion, the authors established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.

Drug Metabolism and Disposition published new progress about Agranulocytosis. 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

Koenigs, Luke L. published the artcileElectrospray Ionization Mass Spectrometric Analysis of Intact Cytochrome P450: Identification of Tienilic Acid Adducts to P450 2C9, Computed Properties of 40180-04-9, the main research area is cytochrome P450 tienilate adduct mass spectrometry.

A general scheme for the purification of baculovirus-expressed cytochrome P450s (P450s) from the crude insect cell pastes has been designed which renders the P450s suitable for anal. by high-performance liquid chromatog. (HPLC) electrospray ionization mass spectrometry (ESI-MS). An HPLC/ESI-MS procedure has been developed to analyze small amounts of intact purified P 450 (P450s cam-HT, 1A1, 1A2, 2A6, 2B1, 2C9, 2C9 C175R, 3A4, 3A4-HT) and rat NADPH cytochrome P 450 reductase (P 450 reductase). The exptl. determined and predicted (based on the amino acid sequences) mol. masses (MMs) of the various proteins had identical rank orders. For each individual protein, the difference between the exptl. determined (±SD, based on experiments performed on at least 3 different days) and predicted MMs ranged from 0.002 to 0.035%. Each exptl. determined MM had a standard deviation of less than 0.09% (based on the charge state distribution). Application of this HPLC/ESI-MS technique made the detection of the covalent modification to P 450 2C9 following mechanism-based inactivation by tienilic acid possible. In the absence of glutathione, three P 450 2C9 species were detected that produced ESI mass spectra corresponding to native P 450 2C9 and both a monoadduct and a diadduct of tienilic acid to P 450 2C9. In the presence of glutathione, only native P 450 2C9 and the monoadduct were detected. Based on the observed mass shifts for the P 450 2C9/tienilic acid adducts, a mechanism for the inactivation of P 450 2C9 by tienilic acid is proposed.

Biochemistry published new progress about Molecular weight. 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, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Mersch-Sundermann, Volker published the artcileSOS induction in Escherichia coli and Salmonella mutagenicity: a comparison using 330 compounds, SDS of cas: 40180-04-9, the main research area is SOS induction Escherichia Salmonella mutagenicity.

To examine the concordance of two microbial genotoxicity short-term assays, 330 exptl. results for the SOS chromotest using tester strain Escherichia coli PQ37 were compared with the results of the Salmonella/mammalian microsome mutagenicity assay with Salmonella typhimurium TA97, TA98, TA100, TA102, TA104, TA1535, TA1537 and/or TA1538. With respect to qual. features, the concordance between SOS chromotest and Salmonella mutagenicity test results was 86.4% (sensitivity, 78.6%; specificity, 100%; χ2 = 188.6). None of the non-mutagens (N = 120) were able to induce the SOS system. Addnl., 45 of the 210 S. typhimurium mutagens (21.5%) did not induce the SOS repair system. On closer examination, the majority of these 45 compounds (84%) were mutagens with activities between 0.001 and 10 rev/nmol. Even though the exptl. protocols of both systems were not standardized, the correlation coefficient for the exptl. results of the two test systems was 0.7 for the 330 chems. Except for aliphatic epoxides (r = 0.47), the mutagenicity/SOS induction correlations for congeneric data sets (polycyclic aromatic hydrocarbons, nitroarenes, nitroarenofurans, mycotoxins) were even better (r = 0.72-0.95). Addnl., computer automated structure evaluation (CASE) analyses of the nature of the structural determinants associated with each endpoint indicate extensive homologies. The data can be taken to indicate that the two phenomena reflect common mechanisms of action.

Mutagenesis published new progress about Escherichia coli. 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

Kobayashi, Kaoru published the artcileCytotoxic effects of benzbromarone and its 1′-hydroxy metabolite in human hepatocarcinoma FLC4 cells cultured on micro-space cell culture plates, Formula: C13H8Cl2O4S, the main research area is benzbromarone hydroxybenzbromarone CYP3A protein glutathione hepatocellular carcinoma anticancer.

Treatment with benzbromarone (BBR), a potent uricosuric drug, can be associated with liver injury. Recently, we reported that culture of human hepatocellular carcinoma FLC-4 cells on micro-space cell culture plates could increase the functional expression of drug-metabolizing enzymes including CYP3A4 and CYP2C9, which are involved in 1′-hydroxylation and 6-hydroxylation of BBR, resp. Therefore, we examined whether BBR and its two metabolites (1′-hydroxy BBR and 6-hydroxy BBR) have cytotoxic effects in FLC4 cells cultured on micro-space cell culture plates. The present study showed that BBR and 1′-hydroxy BBR, but not 6-hydroxy BBR, have cytotoxic effects in cells cultured on micro-space cell culture plates. BBR-induced cytotoxicity was decreased by CYP3A inhibitors (itraconazole and ketoconazole), an Nrf2 activator (tert-butylhydroquinone) and a GSH precursor (N-acetyl-L-cystein). In contrast, BBR-induced cytotoxicity was increased by a GSH biosynthesis inhibitor (buthionine sulfoximine) and an inhibitor of NAD(P)H quinone oxidoreductase 1 (dicoumarol). These results suggested that metabolic activation of 1′-hydroxy BBR via CYP3A, formation of quinone metabolites and the decrease in GSH levels were involved in the BBR-induced cytotoxicity observed in FLC4 cells cultured on micro-space cell culture plates.

Drug Metabolism and Pharmacokinetics published new progress about Antitumor 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, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Aslam, Sana published the artcileAnticancer activity of structural hybrids of various 5/6-memberedheterocycles with pyrazolobenzothiazine 5,5-dioxide, Category: benzothiophene, the main research area is human gastric liver colon carcinoma memberedheterocycle pyrazolobenzothiazine dioxide anticancer.

Thiophene, furan, coumarin and pyrazolobenzothiazine are well familiar for their biol. activities. In this research, pyrazolobenzothiazine ring system is hybridized with various S, N & O-containing heterocycles and the resulting compounds were screened for their anticancer activity against six different cancer cell lines i.e., KB (human oral carcinoma cells), MCF-7(human breast carcinoma cells), A549 (human alveolar adenocarcinoma cells), Hep-G2 (liver carcinoma cells), SGC-7901(human gastric carcinoma cells) and S1 (human colon carcinoma cells) using MTT assay. Most of the compounds exhibited good activity against KB, S1 and A549 cancer cell lines. 5k and 5p appeared as potent inhibitors of KB cell line with IC50 values 2.78 and 4.39 μM resp., 5q was a potent inhibitor of MCF-7 (IC50 value = 13.64 μM) and 5j an excellent inhibitor of A549 cell line having IC50value of 1.03 μM. 5p and 5q were inhibitors of S1 cell line (IC50 values of 8.29 μM and 7.69 μM resp.), whereas, 5o and 5q as inhibitors of Hep-G2 cell line were discovered. A number of compounds show activity exceeding that of 5-fluoruracil in different cell assays. The most potently active compounds, 5j, 5p and 5q, exhibited selectivity in targeting cancerous cells as compared to normal human PBM cells while, 5k and 5o displayed significant toxicity in normal cells.

Pakistan Journal of Pharmaceutical Sciences published new progress about Antitumor agents. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Liang, Jinghui published the artcileDesign and development of novel fasudil derivatives as potent antibreast cancer agent that improves intestinal flora and intestinal barrier function in rats, Application In Synthesis of 1468-83-3, the main research area is breast cancer fasudil invasion microbiota migration ROCK; ROCK; breast cancer; fasudil; invasion; microbiota; migration.

This study was conducted to develop novel fasudil derivatives after incorporation of substituted thiazoles as potent anti-breast cancer (BC) agents. The compounds were developed using a facile synthetic route in excellent yields. The entire set of developed compounds was tested for inhibitory activity against rho-associated coiled-coil kinase (ROCK; ROCK1 and ROCK2) kinase, where they exhibit potent and selective inhibition of ROCK1 as compared to ROCK2. The most potent ROCK2 inhibitor, compound 6h significantly inhibited the viability of BC cells (MCF-7). It also causes inhibition of migration and invasion of MCF-7 cells. Moreover, the anti-BC activity of compound 6h was studied in 7,12 di-Me Benz(a)anthracene (DMBA)-induced BC in female Sprague Dawley rats. Results suggest that it causes significant improvement in the bodyweight of the animals with a reduction in oxidative stress in the liver and mammary tissues of rats. It showed improvement in the intestinal barrier function of rats by restoring the level of Diamine oxidase, D-lactate, and endotoxin. In western blot anal., it showed improvement in (ZO-1), occludin, and claudin-1 in the colon tissue of the rat as compared to the DMBA group. Our study demonstrated the development of the novel class of fasudil derivatives potent anti-BC agent that improves intestinal flora and intestinal barrier function in rats.

Chemical Biology & Drug Design published new progress about Antitumor 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