- Ring closure strategy leads to potent RIPK3 inhibitors
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Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound 38 exhibited potent activity (EC50 = 0.42 μM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29 cells. Mechanistic studies showed that compound 38 bound to RIPK3 with high affinity (Kd = 7.1 nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound 38 displayed good selectivity over another necroptosis regulator RIPK1 (Kd = 6000 nM). Furthermore, compound 38 demonstrated excellent in vitro safety profiles with minimal inhibition of CYP isozymes and hERG potassium channel. Lastly, compound 38 efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.
- Wu, Shuwei,Xu, Chen,Xia, Kaijiang,Lin, Yu,Tian, Sheng,Ma, Haikuo,Ji, Yuting,Zhu, Fang,He, Sudan,Zhang, Xiaohu
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- HETEROARYL COMPOUNDS AS INHIBITORS OF PROGRAMMED NECROSIS PATHWAY, COMPOSITION AND METHOD USING THE SAME
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The present disclosure provides heteroaryl compounds of Formula (I), processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of diseases and disorders, arising from or related to the programmed necrosis pathway.
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Paragraph 00152; 00155-00156
(2021/07/10)
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- 5-nitro-benzothiophene-2-formic acid and chemical synthesis method thereof
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The invention relates to the technical field of benzothiophene compound production, in particular to 5-nitro-benzothiophene-2-formic acid and chemical synthesis method thereof, the method is simple and low in cost, and a solid foundation is provided for mass production and subsequent research of compound materials. The molecular structure of the 5-nitro-benzothiophene-2-formic acid is shown as a formula 1, and meanwhile, the 5-nitro-benzothiophene-2-formic acid has an activity effect of inhibiting oral tooth streptococcus mutans.
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Paragraph 0023-0024
(2021/05/01)
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- Design, synthesis, and biological evaluation of novel benzo[b]thiophene-diaryl urea derivatives as potential anticancer agents
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A hybrid pharmacophore approach was applied to design and synthesize a series of benzo[b]thiophene-diaryl urea derivatives 17a–g with potential anticancer effect. In vitro antiproliferative activities of all target compounds were evaluated against HT-29 a
- Zarei, Omid,Azimian, Fereshteh,Hamzeh-Mivehroud, Maryam,Shahbazi Mojarrad, Javid,Hemmati, Salar,Dastmalchi, Siavoush
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p. 1438 - 1448
(2020/05/28)
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- Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach
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To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was
- Azimian, Fereshteh,Dastmalchi, Siavoush,Hamzeh-Mivehroud, Maryam,Hemmati, Salar,Shahbazi Mojarrad, Javid
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-
- Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors
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STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7a in vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.
- Cai, Guiping,Yu, Wenying,Song, Dongmei,Zhang, Wenda,Guo, Jianpeng,Zhu, Jiawen,Ren, Yuhao,Kong, Lingyi
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p. 236 - 251
(2019/05/02)
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- Bicyclic heterocyclic anthranilic diamides as ryanodine receptor modulators with insecticidal activity
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The diamide insecticides act on the ryanodine receptor (RyR). The synthesis of various bicyclic anthranilic derivatives is reported. Their activity against the insect ryanodine receptor (RyR) and their insecticidal activity in the greenhouse is presented,
- Jeanguenat, André,Durieux, Patricia,Edmunds, Andrew J.F.,Hall, Roger G.,Hughes, Dave,Loiseleur, Olivier,Pabba, Jagadish,Stoller, André,Trah, Stephan,Wenger, Jean,Dutton, Anna,Crossthwaite, Andrew
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p. 403 - 427
(2016/01/25)
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- Benzo[b]thiophene-2-carboxamide derivatives as potent urotensin-II receptor antagonists
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Members of a series of benzo[b]thiophene-2-carboxamide derivatives, possessing an N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl) group, were synthesized and evaluated as urotensin-II receptor antagonists. The results show that these substances have potent UT binding affinities. Observations made in a systematic SAR investigation of the effects of a variety of substituents (R1and R2) at the 5- and 6-positions in the benzo[b]thiophene-2-carboxamide moiety on UT binding affinities led to identification of the 5-cyano analog 7f as a highly potent UT antagonist with an IC50value of 25?nM. Despite having a good metabolic stability, 7f is a potent inhibitor of CYP isozyme and displays an unsuitable PK profile.
- Lim, Chae Jo,Woo, Seong Eun,Ko, Su Ik,Lee, Byung Ho,Oh, Kwang-Seok,Yi, Kyu Yang
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p. 4684 - 4686
(2016/09/13)
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- Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors
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Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in DMSO at 130°C provides rapid access to 3-aminobenzo[b]thiophenes in 58-96% yield. This transformation has been applied in the synthesis of the thieno
- Bagley, Mark C.,Dwyer, Jessica E.,Molina, Maria D. Beltran,Rand, Alexander W.,Rand, Hayley L.,Tomkinson, Nicholas C. O.
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p. 6814 - 6824
(2015/06/25)
-
- Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway
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Signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for cancer therapy. In this study, a series of 2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives (CBT) were designed to inhibit the STAT3 SH2 domain phosphorylation site Try 705. We demonstrated that incorporation of basic flexible groups through amide bond linkage to benzo[b]thiophene 1,1-dioxide (BTP) achieved compounds with higher antiproliferative potency than BTP itself. The most potent compound 6o, as indicated from luciferase reporter gene assay, inhibited the STAT3 pathway by decreasing the phosphorylation level of STAT3 Tyr705, while the phosphorylation level of other upstream tyrosine kinases in this pathway was not significantly inhibited. Compound 6o was also shown to trigger ROS generation and accumulation, thus consequently attributed partially to the observed cell apoptosis. This study provided important structural information for the development of inhibitors targeting the STAT3 pathway.
- Ji, Peng,Xu, Xin,Ma, Shuhua,Fan, Junchao,Zhou, Qiang,Mao, Xinliang,Qiao, Chunhua
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supporting information
p. 1010 - 1014
(2015/09/22)
-
- METHOD FOR PROMOTING PLANT GROWTH
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The present invention provides a method for promoting plant growth, which comprises treating a plant with at least one compound selected from a group consisting of a compound represented by the following Formula (1): and an agriculturally acceptable salt thereof, provided that a method for promoting plant growth which comprises treating plants with a compound corresponding to any one of the following (1) to (5) and an agriculturally acceptable salt thereof is excluded: (1) 4-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, (2) 5-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, (3) 6-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, (4) 7-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, and (5) Benzo[b]thiophene-2-carboxylic acid.
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-
Paragraph 0272; 0273
(2015/11/16)
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- Design, synthesis, and in vitro antiproliferative activity of novel Dasatinib derivatives
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Two series of novel Dasatinib derivatives have been designed and synthesized, with their in vitro cytostatic effect screened on human chronic myeloid leukemia cell line K562 and human myeloid leukemia cell line U937. Some target compounds demonstrated sig
- Cai, Jin,Zhang, Shaoning,Zheng, Ming,Wu, Xiaoqing,Chen, Junqing,Ji, Min
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scheme or table
p. 806 - 810
(2012/03/26)
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- A straightforward expeditious synthesis of 5-nitrobenzo[b]thiophene-2- carbaldehyde
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A high yielding one-pot synthesis of 5-nitrobenzo[b]thiophene-2- carbaldehyde is reported using the readily available,cheap starting material 2,5-dihydroxy-1,4-dithiane and 2-chloro-5-nitrobenzaldehyde.
- Wei, Hongtao,Sun, Min,Ji, Min
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scheme or table
p. 359 - 360
(2009/12/07)
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- Solvent-free microwave synthesis of 3-(4-benzo[b]-thiophene-2-carbonyl)-1-piperazinyl-1-benzo[b]thiophen-2-YL-1-propanones. New hetero bis-ligands with potential 5-HT1A serotonergic activity
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A novel series of 2-benzothiophenealkylpiperazine derivatives 11 (a-d) with potential affinity at 5-HT1A serotonin receptors have been synthesized via solvent-free, microwave-promoted Michael addition of benzo[b]thiophene piperazine derivatives 6(a-c) to substituted benzo[b]thiophen-2-yl propenones 10(b,c).
- Pessoa-Mahana, Hernan,Kosche C., Johann,Ron H., Nadia,Recabarren-Gajardo, Gonzalo,Saitz B., Claudio,Araya-Maturana, Ramiro,Pessoa-Mahana, C. David
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experimental part
p. 1913 - 1929
(2009/04/06)
-
- 6-(4-Chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist
-
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.
- Tavares, Francis X.,Al-Barazanji, Kamal A.,Bishop, Michael J.,Britt, Christy S.,Carlton, David L.,Cooper, Joel P.,Feldman, Paul L.,Garrido, Dulce M.,Goetz, Aaron S.,Grizzle, Mary K.,Hertzog, Donald L.,Ignar, Diane M.,Lang, Daniel G.,McIntyre, Maggie S.,Ott, Ronda J.,Peat, Andrew J.,Zhou, Hui-Qiang
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p. 7108 - 7118
(2011/05/18)
-
- AMINOPYRIMIDINE COMPOUNDS AND METHODS OF USE
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The invention relates to aminopyrimidine compounds useful for treating diseases mediated by polo-like kinase 1 (Plk1). The invention also relates to the therapeutic use of such aminopyrimidine compounds and compositions thereof in treating disease states associated with abnormal cell growth and unwanted cell proliferation.
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Page/Page column 27
(2010/11/08)
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- Synthesis and cytotoxic activity of lipophilic sulphonamide derivatives of the benzo[b]thiophene 1,1-dioxide
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In the search of new compounds with antineoplastic activity, we have analysed the effect of several structural modifications on the nucleus 6-benzo[b]thiophenesulphonamide 1,1-dioxide on its cytotoxic activity on tumour cells. Lipophilic substituents on t
- Villar,Encio,Migliaccio,Gil,Martinez-Merino
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p. 963 - 968
(2007/10/03)
-
- Novel benzothienyl or indole derivatives, preparation and use thereof as inhibitors of prenyl transferase proteins
-
The invention concerns compounds of general formula (1), wherein, in particular; W represents H, SO2R5. CO(CH2)nR5, (CH2)nR6, CS(CH2)nR5; X represents S or NH; Y represents (CH2)p, CO, (CH2)pCO, CH═CH—CO; Z represents a hetcrocycle, imidazole, benzimidazole, isoxazole, tetrazole, oxadiazole, thiadazole, pyridine, quinazoline, quinoxaline, quinoline, thiophene; R1 represents COOR6, CONR6R7, CO—NH—CH(R6)—COOR7, CH2NR6R7, CH2OR6, (CH2)pR6, CH═CHR6; R2 represents in particular hydrogen, C1-C10 alkyl, a substituted or unsubstituted phenyl; R5 and R6 represents hydrogen, C1—C6 alkyl; R5 represents a substituted or unsubstituted phenyl or naphthyl; R6 and R7, identical or different, represent hydrogen, C1—C15 alkyl, a hetcrocycle. an aryl; n represents 0 to 10; p represents 1 to 6.
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-
-
- 4-Aryl-1-(indanmethyl, dihydrobenzofuranmethyl or dihydrobenzothiophene-methyl) piperazines
-
4-Aryl-1-(indanmethyl, dihydrobenzofuramethyl or dihydrobenzothiophenemethyl) piperidine, -tetrahydropyridine or -piperazine compounds of general formula (I) wherein one of X and Y is CH2, and the other one is CH2, O or S; Z is N, C, CH or COH; Ar is an optionally substituted aryl group; R1is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, acyl, thioacyl, alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl, a group R9VCO— where V is O or S and R9is alkyl or aryl, or a group R10R11NCO— or R10R11NCS— wherein R10and R11are hydrogen, alkyl or aryl, or R10and R11are linked to form a ring; R2is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; or R1and R2are linked to form a ring; R3-R5are hydrogen, halogen, alkyl, alkylcarbonyl, phenylcarbonyl, alkoxy, alkylthio, hydroxy, alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkylalkyl or nitro; R6and R7are hydrogen or alkyl or they are linked to constitute a 3-7-membered ring; R8is hydrogen or alkyl; have effects at central serotonergic receptors and are therefore useful in the treatment of certain psychic and neurologic disorders.
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-
- Synthesis of new 5-substitutedbenzo[b]thiophene derivatives
-
Previous works of our group have dealt with the synthesis of 1-(aryl)-3-[4-(aryl)piperazin-1-yl]propane derivatives in the search for new and efficient antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT1A receptor afinity [1-4]. From these studies we concluded that the 3-[4-(aryl)piperazin-1-yl]-l-(benzo[b]thiophen-3-yl)propane derivatives led to the best results. The continuation of this research project required the preparation of some new 3-acyl-5-substituted benzo[b]thiophenes with a wide variety of substituents at the 5 position, ranging from nitro to hydroxyl derivatives. To obtain these derivatives we acylated the corresponding 5-substituted benzo[b]thiophenes when it was possible.
- Perez-Silanes,Martinez-Esparza,Oficialdegui,Villanueva,Orus,Monge
-
p. 1025 - 1030
(2007/10/03)
-
- Benzothiophene derivatives and corresponding use and composition
-
Benzothiophene derivative compounds and corresponding use and composition; the compounds respond to formula (I): where Z is: —CO—, —CH(OR6)—, —C(NOR7)—; R1is: H, C1-C6alkyl, halogen, or —OR8/sub
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- The synthesis of 5-hydroxy-2,3-dihydrobenzo(B)thiophene (1) via an efficient one step preparation of 5-nitro-benzo(B) thiophene-2-carboxylate (3A)
-
The preparation of 5-hydroxy-2,3-dihydrobenzothiophene 1 from 5-nitro-benzothiophene-2-carboxylate 3a is described along with an efficient one pot synthesis of 3a.
- Zambias,Hammond
-
p. 959 - 964
(2007/10/02)
-
- Synthesis and in vitro LTD4 antagonist activity of bicyclic and monocyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides
-
The dissociation constants (K(B)) at the LTD4 receptor on guinea pig trachea of a series of monocyclic and bicyclic cyclopentylurathane and cyclopentylacetamide N-arylsulfonyl amides have been measured. The K(B) was found to be remarkably toler
- Matassa,Brown,Bernstein,Shapiro,Maduskuie Jr.,Cronk,Vacek,Yee,Snyder,Krell,Lerman,Maloney
-
p. 2621 - 2629
(2007/10/02)
-