Category: benzothiophene

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

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

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

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

Mancy, Annah published the artcileThe Substrate Binding Site of Human Liver Cytochrome P450 2C9: An Approach Using Designed Tienilic Acid Derivatives and Molecular Modeling, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cytochrome P450 2C9 tienilate derivative association.

Biochem. experiments, using the well-defined human liver CYP2C9 expressed in yeast, and mol. modeling techniques were used to derive a predictive model for substrates of CYP2C9. The ability of 10 2-aroylthiophenes related to tienilic acid to act as substrates for CYP2C9 was studied. Four of them were original compounds that were synthesized and completely characterized by several spectroscopic techniques. In these 10 compounds various chem. functions, such as ester, amide, alc., phenol, ether or tetrazole functions, replaced the OCH2COOH function of tienilic acid. Among them, only the derivatives containing an acidic function (carboxylic acids, phenol, and tetrazole whose pKas are 4.8, 6.3, and 3.8, resp.) underwent a 5-hydroxylation of their thiophene ring like tienilic acid. Despite their close structural analogy with tienilic acid, all of the other compounds not only did not undergo any 5-hydroxylation of their thiophene ring but also failed to act as inhibitors of CYP2C9. These results strongly suggested that the presence, at pH 7.4, of a neg. charge on the substrates is a very important feature in its recognition by CYP2C9. In fact, the four new substrates of CYP2C9 described in this study, a carboxylic acid, phenol, and tetrazole derivative, each of which is related to tienilic acid, and the antiinflammatory drug, suprofen (with Km between 12 and 130 μM and kcat between 0.2 and 1.3 min-1), as well as almost all CYP2C9 substrates reported in the literature, exhibit a pKa below 7 (except phenytoin whose pKa is 8.1). They mainly exist as anions at physiol. pH. By using mol. modeling techniques, 12 CYP2C9 substrates were superimposed with respect to their hydroxylation site and fitted onto templates, which were rigid mols. such as (S)-warfarin and phenytoin. It was thus possible to arrange them in order that all their anionic sites were at a distance around 4 Å from a common point (a putative cationic site of the protein) in space. These results provide a model of the substrate binding site of CYP2C9, in which substrates interact through their anionic site A- with a cationic residue of the CYP2C9 protein C+. In that model, the distance between the hydroxylation site (Hy) and the anionic site (A-) is 7.8 Å, and the ∠HyA-C+ angle is 82°.

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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Lewis, D. F. V. published the artcileOn the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics. Towards the prediction of human P450 substrate specificity and metabolism, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is mammal microsome cytochrome P450 isoform substrate specificity metabolism.

The characteristics of mammalian microsomal P 450 xenobiotic substrates are described, particularly with reference to the major P 450 isoforms associated with drug metabolism in humans. It is further reported that a relatively small number of mol., electronic, and physico-chem. properties are required to discriminate between chems. that exhibit specificity for human P 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Mol. templates of superimposed substrates are shown to be complementary with the putative active sites of the relevant enzymes, thus enabling a possible prediction of P 450 specificity from structure. Factors contributing to metabolic clearance and binding affinity are also discussed, and methods for their calculation are described.

Biochemical Pharmacology published new progress about Sodium channel blockers. 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

Mansuy, Daniel published the artcileNew biological reactive intermediates. Metabolic activation of thiophene derivatives, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is metabolic activation thiophene derivative review.

A review and discussion with 16 references Metabolic activation of tienilic acid and its isomer, metabolic oxidation of thiophene in vivo and in vitro, inactivation and alkylation of P 450 2C9 upon metabolic activation of tienilic acid, thiophene sulfoxides – a new class of reactive metabolites were discussed.

Advances in Experimental Medicine and Biology published new progress about Biochemical alkylation. 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 of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Pearson, R. M. published the artcileBiochemical and hematological changes induced by tienilic acid combined with propranolol in essential hypertension, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilate propranolol essential hypertension.

In a double blind crossover trial, in which 16 patients with essential hypertension received placebo, tienilic acid (I) [40180-04-9] (250 mg/day), propranolol (II) [525-66-6] (80 mg twice daily), or I (250 mg/day) combined with II (80 mg twice daily), average blood pressure in the lying position was 169/98, 157/94, 159/90, and 142/86 mm Hg for placebo, I-, II-, and I combined with II-treated patients, resp. Thus, the effects of I and II on blood pressure were additive, and no interactions between I and II were observed I reduced serum water from 0.33 to 0.18 mmol/L and induced hypokalemia which was corrected by II. Basophil count and Hb were lower after I treatment than they had been at the start of the study.

Lancet published new progress about Essential hypertension. 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

Lewis, David F. V. published the artcileQuantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is QSAR human cytochrome P450 CYP2 family enzyme.

The results of quant. structure-activity relationship (QSAR) studies on substrates of human CYP2 family enzymes are reported, together with those of a small number of CYP2A6, CYP2C19 and CYP2D6 inhibitors. In general, there are good correlations (R=0.90-0.99) between binding affinity (based on Km or KD values) and various parameters relating to active site interactions such as hydrogen bonding and π-π stacking. There is also evidence for the role of compound lipophilicity (as determined by either log P or log D7.4 values) in overall substrate binding affinity, and this could reflect the desolvation energy involved in substrate interaction within the enzyme active site. It is possible to estimate the substrate binding energy for a given P 450 from a combination of energy terms relating to hydrogen bonding, π-π stacking, desolvation and loss in rotatable bond energy, which agree closely (R=0.98) with exptl. data based on either Km or KD values. Consequently, it is likely that active site interactions represent the major contributory factors to the overall binding affinities for human CYP2 family substrates and, therefore, their estimation is of potential importance for the development of new chem. entities (NCEs) as this can facilitate an assessment of likely metabolic clearance.

Toxicology in Vitro published new progress about Free energy of binding. 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

Minoletti, Claire published the artcileComparison of the Substrate Specificities of Human Liver Cytochrome P450s 2C9 and 2C18: Application to the Design of a Specific Substrate of CYP 2C18, Synthetic Route of 40180-04-9, the main research area is substrate specificity liver cytochrome P450 2C18; aroylthiophene P450 hydroxylation substrate preparation.

A series of 2-aroylthiophenes derived from tienilic acid by replacement of its OCH2COOH substituent with groups bearing various functions have been synthesized and studied as possible substrates of recombinant human liver cytochrome P450s 2C9 and 2C18 expressed in yeast. Whereas only compounds bearing a neg. charge acted as substrates of CYP 2C9 and were hydroxylated at position 5 of their thiophene ring at a significant rate, many neutral 2-aroylthiophenes were 5-hydroxylated by CYP 2C18 with kcat values of >2 min-1. Among the various compounds that were studied, those bearing an alc. function were the best CYP 2C18 substrates. One of them, compound 3, which bears a terminal O(CH2)3OH function, appeared to be a particularly good substrate of CYP 2C18. It was regioselectively hydroxylated by CYP 2C18 at position 5 of its thiophene ring with a KM value of 9 ± 1 μM and a kcat value of 125 ± 25 min-1, which are the highest described so far for a CYP 2C. A comparison of the oxidations of 3, by yeast-expressed CYP 1A1, 1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, and 3A5, showed that only CYP 2C8, 2C18, and 2C19 were able to catalyze the 5-hydroxylation of 3. However, the catalytic efficiency of CYP 2C18 for that reaction was considerably higher (kcat/KM value being 3-4 orders of magnitude larger than those found for CYP 2C8 and 2C19). Several human P450s exhibited small activities for the oxidative O-dealkylation of 3. The four recombinant CYP 2Cs were the best catalysts for that reaction (kcat between 1 and 5 min-1) when compared to all the P450s that were tested, even though it is a minor reaction in the case of CYP 2C18. All these results show that compound 3 is a new, selective, and highly efficient substrate for CYP 2C18 that should be useful for the study of this P 450 in various organs and tissues. They also suggest some key differences between the active sites of CYP 2C9 and CYP 2C18 for substrate recognition.

Biochemistry published new progress about Hydroxylation, enzymic. 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