- Design, synthesis, docking, molecular dynamics and bioevaluation studies on novel N-methylpicolinamide and thienopyrimidine derivatives with inhibiting NF-κB and TAK1 activities: Cheminformatics tools RDKit applied in drug design
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Using cheminformatics tools RDKit and literature investigation, four series of 24 thienopyrimidine/N-methylpicolinamide derivatives substituted with pyrimidine were designed, synthesized and evaluated for activities against three cancer cell lines (MDA-MB-231, HCT116 and A549), TAK1 kinase and NF-κB signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-κB signaling pathway with the IC50 values of 0.58 and 0.84 μM. Moreover, 38 can induce cell cycle arrest of A549 cells at the G2/M checkpoint with 30.57% and induce apoptosis (34.94%) in a concentration-dependent manner. And western blot showed that compound 38 could inhibit TNF-α-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation and TAK1 phosphorylation, and reduce the expression of p65. What's more, the studies of docking, molecular dynamics, MM/PBSA and frequency analysis theoretically supported the conclusions of the bioevaluation.
- Wang, Linxiao,Zhang, Qian,Wang, Zhe,Zhu, Wufu,Tan, Ninghua
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- Synthesis and antimicrobial activity of novel thienopyrimidine linked rhodanine derivatives
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This work presents the preparation of a new series of N-(substituted phenyl)-2-(4-oxo-5-(4-(thieno[2,3-d]-pyrimidin-4-yloxy)benzylidene)-2-thioxothiazolidin-3-yl)acetamide derivatives (8a-8l). A condensation reaction of thienopyrimidin-2-thioxothiazolidin
- Kerru, Nagaraju,Maddila, Surya Narayana,Maddila, Suresh,Sobhanapuram, Sreedhar,Jonnalagadda, Sreekantha B.
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- Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor
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We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).
- Fyfe, Tim J.,Kellam, Barrie,Mistry, Shailesh N.,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 474 - 490
(2019/03/07)
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- Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors
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The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.
- Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Schiaffino Ortega, Santiago,Chayah, Mariem,Kimatrai Salvador, Maria,Lopez-Cara, Luisa Carlota,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Ronca, Roberto,Bortolozzi, Roberta,Mariotto, Elena,Mattiuzzo, Elena,Viola, Giampietro
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supporting information
p. 1274 - 1290
(2019/01/30)
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- Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors
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Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were
- Wang, Linxiao,Xu, Shan,Chen, Xiuying,Liu, Xiaobo,Duan, Yongli,Kong, Dejia,Zhao, Dandan,Zheng, Pengwu,Tang, Qidong,Zhu, Wufu
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p. 245 - 256
(2017/12/06)
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- Iridium complex containing thieno-[2,3-d] pyrimidine group and application in electroluminescence device
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The invention disclose an iridium complex containing a thieno-[2,3-d] pyrimidine group and application of the iridium complex as a phosphorescence object material in an electroluminescence device. Main ligands in the series of iridium complex molecules are derivatives containing thieno-[2,3-d] pyrimidine heterocyclic rings. Auxiliary ligands are diacetone, tetramethyl-3,5-heptanedione or 2-pyridine carboxylic acid. The iridium complex has the characteristics of high luminous efficiency, stable chemical property, easy purification and the like, and the application of the iridium complex as thephosphorescence object material in an electroluminescence device has excellent luminous efficiency, electron mobility and stability. Through the modification of the main ligands, the luminous wavelength and efficiency of the complex can be adjusted in a visible light band.
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Paragraph 0051-0053
(2018/03/09)
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- Synthesis and antioxidant evaluation of a new class of thienopyrimidinerhodanine hybrids
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Background: Antioxidants are proficient of stabilizing agents in the target cells and biological systems. The homeostatic equilibrium between the reactive oxygen species and endogenous antioxidants is important in maintaining healthy tissues. As some antioxidant agent’s show improved resistance, it is necessary to design the new heterocyclic molecules to form potent antioxidant agents with promising pharmacological applications. Moreover, thienopyrimidine derivatives has been the subject of much research due to their significance in different applications and their extensive potential pharmacological and medicinal activities like antibacterial, antifungal, anticancer, anticonvulsant, anti-inflammatory, analgesic, anti-viral, anti-oxidant, anti-diabetic and antimalarial properties. Although, recently rhodanine was reported as privileged hybrid in drug discovery and exhibited pharmacological activities such as anti-malarial, antibacterial, antiviral, antidiabetic agents. Hence, the development of new molecules within the scope of synthetic procedure of thienopyrimidine scaffold for heterocyclic synthesis would be worthy and well desired. Methods: All the target thienopyrimidine-rhodanine derivatives (5a-l) prepared from the Knoevenagel condensation with different substituted benzaldehydes in the presence of glacial acetic acid and 3-(thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (4). Although, all the synthesized compounds tested for their anti-oxidant activity investigated using DPPH radical scavenging, nitric oxide (NO) and ABTS activity. Results: All the thienopyrimidine-rhodanine derivatives (5a-l) were evaluated for their in vitro anti-oxidant activity. In fact, (Z)-5-(4-methylbenzylidene)-3-(thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (5c) with IC50 value 17.64 ± 0.06 μg/mL and (Z)-5-(2-nitrobenzylidene)-3-(thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (5j) with IC50 value 17.54 ± 0.23μg/mL showed excellent antioxidant activity nearly similar to the standard drug as an ascorbic acid (IC50 = 17.45 ± 0.03μg/mL). Conclusion: The objective of the present work was to design, synthesis and screened for their antioxidant activities of novel thienopyrimidine containing rhodanine derivatives with the hope of discovering new structure leads as the most potent antioxidant agents. Our aim has been achieved by the synthesis of thienopyrimidines with diver functionalities by exploiting 2-thioxothiazolidin-4-one chemistry and tested for antioxidant activity. The compounds 5c and 5j were found most potent activity compare to the standard ascorbic acid. Furthermore, the electron withdrawing groups at position-4 in benzene ring enhanced the activity, whereas the compounds 5d, 5f, 5i and 5l showed good activity all the three radical scavenging methods.
- Nagaraju, Kerru,Bhaskaruni, Venkata H. S. S.,Kishore, Ravada,Maddila, Suresh,Singh, Parvesh,Jonnalagadda, Sreekantha B.
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p. 118 - 126
(2018/03/21)
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- A JAK/STAT3 phosphorylation inhibitor and its preparation method and use thereof
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The invention provides a JAK/STAT3 phosphorylation inhibitor as well as a preparation method and application thereof. The structural formula of the JAK/STAT3 phosphorylation inhibitor is as shown in a formula I, wherein X is selected from S or O; Y and Z
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- Preparation and application of thiophene pyrimindine compound containing heteroaryl amide structure
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The invention relates to a thiophene pyrimindine compound containing a heteroaryl amide structure shown in the general formula I, and a pharmaceutically acceptable salt, an aquo-complex, a solvate and a predrug of the thiophene pyrimindine compound containing the heteroaryl amide structure, wherein the implications of the substituent group R1, X, Y, D and Z are shown in the description. The invention further relates to a strong effect of inhibiting c-Met kinase of the compound shown in the general formula I, and also relates to application of the compound and the pharmaceutically acceptable salt, the aquo-complex, the solvate and the predrug of the thiophene pyrimindine compound to preparing a medicine used for treating diseases caused by abnormal high expression of the c-Met kinase, particularly application to preparing a medicine for treating and/or preventing cancers.
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- A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
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Recently, a novel negative allosteric modulator (NAM) of the D2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.
- Fyfe, Tim J.,Zarzycka, Barbara,Lim, Herman D.,Kellam, Barrie,Mistry, Shailesh N.,Katrich, Vsevolod,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 174 - 206
(2018/05/14)
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- HETEROCYCLIC COMPOUNDS, PROCESS FOR PREPARATION OF THE SAME AND USE THEREOF
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The present invention provides a heterocyclic compound represented by the formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions thereof, and their use in preparing a medicament for the prevention and/or treatment of central nervous system disease.
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Paragraph 0352; 0355; 0356
(2017/07/15)
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- Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication
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A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of ～450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50value in the sub-micromolar range and a good selectivity index. Different series of novel thieno-pyrimidine derivatives were designed and synthesised; several new structures showed antiviral activity in the low or sub-micromolar range.
- Bassetto, Marcella,Leyssen, Pieter,Neyts, Johan,Yerukhimovich, Mark M.,Frick, David N.,Brancale, Andrea
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supporting information
p. 31 - 47
(2016/08/01)
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- Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase
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A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
- Tarver, James E.,Pabba, Praveen K.,Barbosa, Joseph,Han, Qiang,Gardyan, Michael W.,Brommage, Robert,Thompson, Andrea Y.,Schmidt, James M.,Wilson, Alan G.E.,He, Wei,Lombardo, Victoria K.,Carson, Kenneth G.
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p. 1525 - 1528
(2016/07/27)
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- A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines
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Abstract The synthesis of 5-hydroxymethyl-, 5-acetoxymethyl-, 5-formyl- and 5-cyanothieno[2,3-d]pyrimidines, the (methyl)-5-carboxylate, and the respective amide functionality was accomplished by building up the functionalized molecule starting from appropriately substituted thiophene precursors. A similar strategy starting from the pyrimidine precursor and subsequent direct functionalization (formylation and cyanation) of the thieno[2,3-d]pyrimidine parent compound in position 5 was found to be less feasible.
- Wilding, Birgit,Faschauner, Stefan,Klempier, Norbert
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supporting information
p. 4486 - 4489
(2015/06/30)
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- ANTI-CANCER ACTIVITY OF NOVEL BICYCLIC HETEROCYCLES
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The present invention relates to compound of formula I, II, III, or IV, and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof, Formulas (I), (II), (III) and (IV) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and R12 are as defined in the claim 1 or as described in detail in the description of the invention, and to the use of said compounds to treat or prevent proliferative disorders and their use to manufacture a medicine to treat or prevent proliferative disorders, particularly cancer such as leukemia. The present invention also relates to pharmaceutical compositions of said compounds and the use of said pharmaceutical compositions to treat or prevent proliferative disorders. The present invention further relates to the use of said compounds as biologically active ingredients, more specifically as medicaments for the treatment of proliferative disorders and pathologic conditions such as, but not limited to, cancer such as leukemia.
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Paragraph 1228-1230
(2014/04/03)
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- Antiviral Activity of Novel Bicyclic Heterocycles
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The present invention relates to compound of Formula I, II, III, or IV, and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and R12 are as defined in the claim 1 or as described in detail in the description of the invention, and to the use of said compounds to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with RNA-viruses belonging to the family of the Retroviridae, the family of the Flaviviridae and the family of the Picornaviridae and more preferably infections with Human Immunodeficiency Virus 1 (HIV1), Human Immunodeficiency Virus 2 (HIV2), Hepatitis C virus (HCV), Dengue virus, and enteroviruses like Coxsackievirus, Rhinovirus and Poliovirus. The present invention also relates to pharmaceutical compositions of said compounds and the use of said pharmaceutical compositions to treat or prevent viral infections. The present invention further relates to the use of said compounds as biologically active ingredients, more specifically as medicaments for the treatment of viral disorders and pathologic conditions such as, but not limited to, viral infections with Human Immunodeficiency Virus 1 (HIV1), Human Immunodeficiency Virus 2 (HIV2), Hepatitis C virus (HCV), Dengue virus, and enteroviruses like Coxsackievirus, Rhinovirus and Poliovirus.
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Paragraph 1213; 1214; 1215
(2013/07/31)
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- THIAZOLOPYRIMIDINE MODULATORS AS IMMUNOSUPPRESSIVE AGENTS
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The present invention relates to compound of formula I, II, III, or IV, and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and R12 are as defined in the claim 1. The present invention also relates to a method for their preparation, as well as to pharmaceutical compositions thereof. The present invention further relates to the use of said compounds as biologically active ingredients, more specifically as medicaments for the treatment of disorders and pathologic conditions such as, but not limited to, immune and auto-immune disorders, organ and cells transplant rejections.
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Page/Page column 81
(2012/03/10)
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- Synthesis, immunosuppressive activity and structure-activity relationship study of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidine analogues
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The synthesis of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidines is described. The synthetic route allows introducing structural variety at positions 2, 4 and 6 of the scaffold. Evaluation of their immunosuppressive activity in a Mixed Lymphocyte Reaction (MLR) assay revealed that the most potent compound has an IC50-value of 66 nM and therefore deserves attention for further medicinal chemistry optimization.
- Jang, Mi-Yeon,Jonghe, Steven De,Belle, Kristien Van,Louat, Thierry,Waer, Mark,Herdewijn, Piet
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scheme or table
p. 844 - 847
(2010/09/15)
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- Unexpected C - O bond formation in Suzuki coupling of 4-chlorothieno[2,3-d] pyrimidines
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(Chemical Equation Presented) Palladium-catalyzed Suzuki reactions were performed on 4-chlorothieno[2,3-d]pyrimidines under classical heating conditions and under microwave irradiation. Some unexpected results were obtained during this study as two kinds of compounds were isolated depending on the conditions used. A careful investigation of experimental details has shown that the expected CAC bond formation occurred when degassed solvents were used (both in classical and microwave heating) whereas an unexpected CAO bond formation happened when solvents were not degassed with argon-bubbling before use.
- Perspicace, Enrico,Hesse, Stephanie,Kirsch, Gilbert,Yemloul, Mehdi,Lecomte, Claude
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scheme or table
p. 459 - 464
(2009/09/28)
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- 2-AMINOPYRIDINE ANALOGS AS GLUCOKINASE ACTIVATORS
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Provided are compounds that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.
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Page/Page column 61
(2008/12/04)
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- Microwave-assisted synthesis of 2-aminothiophene-3-carboxylic acid derivatives, 3H-thieno[2,3-d]pyrimidin-4-one and 4-chlorothieno[2,3-d]pyrimidine
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A two-minute microwave irradiation allowed the synthesis of several 2-aminothiophene-3-carboxylic acid derivatives. Their efficient transformation to thieno[2,3-d]pyrimidin-4-one and the corresponding 4-chloro derivative is also reported under microwave irradiation.
- Hesse, Stéphanie,Perspicace, Enrico,Kirsch, Gilbert
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p. 5261 - 5264
(2008/02/08)
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- INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
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The invention relates to the inhibition of vascular endothelial growth factor (VEGF) receptor signaling and hepatocyte growth factor (HGF) receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
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Page/Page column 172-173
(2010/02/15)
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- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
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Page/Page column 52
(2010/11/24)
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- New piperidinylamino-thieno[2,3-D] pyrimidine compounds
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The invention relates to 5-HT receptor antagonists. Novel piperidinylamino-thieno [2,3-d]pyrimidine compounds represented by Formula I, and synthesis and uses thereof for treating diseases mediated directly or indirectly by 5-HT receptors, are disclosed.
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- SUBSTITUTED AMINOPYRIMIDINES AS NEUROKININ ANTAGONISTS
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The invention discloses tachykinin receptor antagonists. The tachykinin family of receptors comprising the neurokinins substance P (SP), neurokinin A, and neurokinin B and related neuropeptides that are widely distributed in the peripheral and central ner
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- PREVENTIVES OR REMEDIES FOR MYOCARDITIS, DILATED CARDIOMYOPATHY AND CARDIAC INSUFFICIENCY CONTAINING NF-KAPPA B INHIBITORS AS THE ACTIVE INGREDIENT
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The present invention provides a preventive or therapeutic agents for myocarditis, dilated cardiomyopathy and heart failure comprising NF-κB inhibitors as active ingredients.
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- NF-γ(k)B INHIBITORS CONTAINING INDAN DERIVATIVES AS THE ACTIVE INGREDIENT
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An inhibitor of NF-κB comprising as an active ingredient an indan derivative represented by the general formula (I) or a salt thereof.
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- Thienopyrimidine derivatives
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4-Substituted-thieno[2,3-d], [3,2-d], and [3,4-d]pyrimidines having fungicidal, insecticidal, and miticidal utility are disclosed. Related 3-substituted-thieno[2,3-d], [3,2-d], and [3,4-d]pyrimidin-4-(3H)-imines are useful as fungicides, insecticides, and
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