- 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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p. 1274 - 1290
(2019/01/30)
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- Identification of 4-methoxythieno[2,3-d]pyrimidines as FGFR1 inhibitors
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Aim. To identify novel FGFR1 inhibitors using virtual screening approach. Methods. We used methods of organic synthesis, molecular docking via the Autodock 4.2.6 program package and in vitro biochemical tests with γ-32P. Results. In vitro experiments showed that 9 of 23 tested compounds possess inhibitory activity against FGFR1 with IC50 values in the range from 0.9 to 5.6 μM. Conclusions. Nine FGFR1 inhibitors were developed. The mode of compounds binding with the ATP-acceptor site was determined using molecular docking methods and the dependence of the compounds’ activity on the substituents R1, R4 and R5 was evaluated.
- Balanda, A. O.,Bdzhola, V. G.,Kotey, I. M.,Pletnova, L. V.,Protopopov, M. V.,Prykhod’ko, A. O.,Starosyla, S. A.,Yarmoluk, S. M.
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p. 152 - 162
(2020/06/02)
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- 2-aminothiophene compound preparation method
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The invention discloses a 2-aminothiophene compound preparation method. The method includes the step that ketone, nitrile and sulfur in a mole ratio of 1:1:1 are used as raw materials for preparing 2-aminothiophene compounds through catalytic cyclization. By adoption of ketone, nitrile and sulfur as the raw materials, the method has advantages of simple operating steps, high product yield, low cost and the like, and a high industrial value is achieved.
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Paragraph 0035; 0036
(2019/01/14)
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- Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H
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Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have s
- Kankanala, Jayakanth,Kirby, Karen A.,Huber, Andrew D.,Casey, Mary C.,Wilson, Daniel J.,Sarafianos, Stefan G.,Wang, Zhengqiang
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supporting information
p. 149 - 161
(2017/10/16)
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- THIENOPYRIMIDINONE NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided.
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Paragraph 00371-00138
(2017/07/13)
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- Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines
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An extension of our previous research work has resulted in a number of new ATP-competitive CK2 inhibitors that have been identified among 4-aminothieno[2,3-d]pyrimidine derivatives. The most active compounds obtained in the course of the research are 3-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5e (NHTP23, IC50 = 0.01 μM), 3-(5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5g (NHTP25, IC50 = 0.065 μM) and 3-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5n (NHTP33, IC50 = 0.008 μM). Structure-activity relationships of the tested 4-aminothieno[2,3-d]pyrimidine derivatives have been studied and their binding mode with ATP-acceptor site of CK2 has been proposed. A negative effect of intramolecular hydrogen bonding in the compounds' structure is discussed.
- Ostrynska, Olga V.,Balanda, Anatoliy O.,Bdzhola, Volodymyr G.,Golub, Andriy G.,Kotey, Igor M.,Kukharenko, Olexander P.,Gryshchenko, Andrii A.,Briukhovetska, Nadiia V.,Yarmoluk, Sergiy M.
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p. 148 - 160
(2016/04/05)
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- Expanding the scaffold for bacterial RNA polymerase inhibitors: Design, synthesis and structure-activity relationships of ureido-heterocyclic-carboxylic acids
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The emergence of bacterial resistance requires the development of new antibiotics with an alternative mode of action. Based on class I, developed in our previous study, a new series of RNA polymerase (RNAP) inhibitors targeting the switch region was desig
- Elgaher, Walid A. M.,Fruth, Martina,Groh, Matthias,Haupenthal, Joerg,Hartmann, Rolf W.
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p. 2177 - 2194
(2014/01/06)
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- Novel 4-oxothienopyrimidinyl propanoic acid derivatives as AMPactivated protein kinase (AMPK) activators
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Adenosine 5′-monophosphate (AMP) activated protein kinase (AMPK) is a highly conserved sensor of cellular energy. AMPK has been recognized as a key regulator of mammalian metabolic function and has emerged as an attractive target for the treatment of meta
- Sasmal, Pradip K.,Jaleel, Mahaboobi,Rao, P. Tirumala,Munikumar,Bhattacharya, Megha,Kumar, Nutakki Ravi,Neelima, Poondla,Rawoof, Khaji Abdul,Rao, P. Narasimha,Abbineni, Chandrasekhar,Roshaiah,Sridhar,Kumar, Thammera Ranjith,Vinu, Menon C.A.,Potluri, Vijay,Misra, Parimal,Talwar, Rashmi,Das, Saibal Kumar
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p. 778 - 785
(2014/07/07)
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- RETINOID-RELATED ORPHAN RECEPTOR GAMMA MODULATORS, COMPOSITION CONTAINING THEM AND USES THEREOF
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Provided are retinoid-related orphan receptor gamma(ROR γ) modulators of formula (I), processes for their preparation, pharmaceutical compositions containing them, and their uses in the treatment of diseases mediated by ROR γ.
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Page/Page column 13
(2012/08/08)
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- Synthesis and antimicrobial activity of novel 2-(pyridin-2-yl)thieno[2,3-d] pyrimidin-4 (3H)-ones
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In the present study, some new 2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4(3H) -ones derivatives (IIa-o) were synthesized. The target compounds (IIa-o) were synthesized through the acid catalyzed condensation of 2-cyano, 3-cyano, and 4-cyano-pyridines with various 2-amino-3-carbethoxythiophenes (Ia-e). All thiophene derivatives were synthesized by Gewald reaction. The structures of the newly synthesized compounds were confirmed by UV-Visible, FT-IR, 1H-NMR, and mass spectral studies. All synthesized compounds were evaluated for their antimicrobial activity against various gram-positive and gram-negative bacterial and fungal strains. Amongst the synthesized compounds IIa, IIb, IId, IIe, and IIm were found to be active. TUeBITAK.
- Haswani, Nitin G.,Bari, Sanjaykumar B.
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experimental part
p. 915 - 924
(2012/02/16)
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- Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin- 4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2
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A novel series of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids has been synthesized and tested in vitro towards human protein kinase CK2. It was revealed that the most active compounds inhibiting CK2 are 3-{[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid and 3-{[5-(4-ethoxyphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid (IC 50 values are 0.1 μM and 0.125 μM, respectively). Structure-activity relationships of 28 tested thienopyrimidine derivatives have been studied and binding mode of this chemical class has been predicted. Evaluation of the inhibitors on seven protein kinases revealed considerable selectivity towards CK2.
- Golub, Andriy G.,Bdzhola, Volodymyr G.,Briukhovetska, Nadiia V.,Balanda, Anatoliy O.,Kukharenko, Olexander P.,Kotey, Igor M.,Ostrynska, Olga V.,Yarmoluk, Sergiy M.
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experimental part
p. 870 - 876
(2011/04/22)
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- Synthesis and anti-tumor activities of N′-benzylidene-2-(4- oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetohydrazone derivatives
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A compound with a cyclic thienopyrimidine moiety and an aceto-hydrazone moiety in its chemical structure was discovered in a cell-based screening to have noticeable cytotoxicity on several tumor cell lines. A total of 38 derivatives of this compound were
- Lou, Jiangping,Liu, Zhen,Li, Yan,Zhou, Mi,Zhang, Zhengxi,Zheng, Shu,Wang, Renxiao,Li, Jian
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supporting information; experimental part
p. 6662 - 6666
(2011/12/04)
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- 2-(3,4-dihydro-4-oxothieno[2,3-d]pyrimidin-2-ylthio) acetamides as a new class of falcipain-2 inhibitors. 3. design, synthesis and biological evaluation
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The cysteine protease falcipain-2 (FP-2) of Plasmodium falciparum is a principal cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites, making it become an attractive target enzyme for developing anti-malarial drugs.
- Zhu, Jin,Chen, Tong,Liu, Jie,Ruoqun, Ma.,Lu, Weiqiang,Huang, Jin,Li, Honglin,Li, Jian,Jiang, Hualiang
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experimental part
p. 785 - 797
(2009/05/27)
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- Efficient synthesis of substituted 2-amino-3-carbethoxythiophenes
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A microwave-assisted method for the synthesis of a variety of thiophene o-aminoesters (2a-l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur. Copyright Taylor & Francis Group, LLC.
- Kathiravan,Shishoo,Chitre,Mahadik,Jain
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p. 4273 - 4279
(2008/03/13)
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- Discovery and SAR development of thienopyridones: A class of small molecule AMPK activators
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AMP-activated protein kinase (AMPK) is well established as a sensor and regulator of intracellular and whole-body energy metabolism. A high-throughput screen was performed in order to identify chemotypes that are bound by AMPK. A novel thienopyridone comp
- Zhao, Gang,Iyengar, Rajesh R.,Judd, Andrew S.,Cool, Barbara,Chiou, William,Kifle, Lemma,Frevert, Ernst,Sham, Hing,Kym, Philip R.
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p. 3254 - 3257
(2008/02/08)
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- Aryl alkyl ketones in a one-pot Gewald synthesis of 2-aminothiophenes
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2-Aminothiophene-3-carboxylates bearing various aryl groups at the 4-position are readily obtained in good to moderate yields by the one-pot Gewald reaction of aryl alkyl ketones with ethyl cyanoacetate and elemental sulfur in the presence of morpholinium acetate and excess morpholine. Georg Thieme Verlag Stuttgart.
- Tormyshev, Victor M.,Trukhin, Dmitry V.,Rogozhnikova, Olga Yu.,Mikhalina, Tatiana V.,Troitskaya, Tatiana I.,Flinn, Anthony
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p. 2559 - 2564
(2008/09/16)
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- THIENOPYRIMIDINE DERIVATIVES AS POTASSIUM CHANNEL INHIBITORS
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The present invention provides thienopyrimidine compounds which are potasium channels inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrhythmia are also provided.
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- Pharmaceutically active compounds and methods of use
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New fused thiophene compounds are provided and methods of using those compounds for a variety of therapeutic indications. Compounds of the invention are particularly useful for treatment of neuropathic pain.
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