- Polycyclic N-heterocyclic compounds. Part 84: Reaction of N-(pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-yl)amidines or N-(pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-yl)amidines with hydroxylamine hydrochloride
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The reactions of nine N-(pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-yl)amidines (3) with hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4-oxadiazole-forming r
- Okuda, Kensuke,Ide, Ryota,Uramaru, Naoto,Hirota, Takashi
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- GLUCOSE UPTAKE INHIBITORS AND USES THEREOF
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The present invention relates to novel compounds that modulate cellular glucose uptake by affecting various targets, including, but not limited to those related to glycolysis and known transporters/co-transporters of the GLUT family. The compounds according to the invention are useful for treating cancer such as: neuroendrocrine neoplasms, gastrointestinal stromal tumors (GIST), renal cell carcinoma, paraganglioma, pheochromocytoma, pituitary adenoma, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer sarcoma, head and neck cancer, melanoma, ovarian cancer and other cancers that rely on high levels of glycolysis for survival and proliferation; as well as in treating of autoimmune diseases, inflammation, infectious diseases, and metabolic diseases.
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Paragraph 00486
(2021/05/21)
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- Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase
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Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on
- Massari, Serena,Bertagnin, Chiara,Pismataro, Maria Chiara,Donnadio, Anna,Nannetti, Giulio,Felicetti, Tommaso,Di Bona, Stefano,Nizi, Maria Giulia,Tensi, Leonardo,Manfroni, Giuseppe,Loza, Maria Isabel,Sabatini, Stefano,Cecchetti, Violetta,Brea, Jose,Goracci, Laura,Loregian, Arianna,Tabarrini, Oriana
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- Bioisosteric investigation of ebselen: Synthesis and in vitro characterization of 1,2-benzisothiazol-3(2H)-one derivatives as potent New Delhi metallo-β-lactamase inhibitors
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Carbapenem-resistant Enterobacteriaceae (CRE) producing New Delhi metallo-β-lactamase (NDM-1) cause untreatable bacterial infections, posing a significant threat to human health. In the present study, by employing the concept of bioisosteric replacement of the selenium moiety of ebselen, we have designed, synthesized and characterized a small compound library of 2-substituted 1,2-benzisothiazol-3(2H)-one derivatives and related compounds for evaluating their cytotoxicity and synergistic activity in combination with meropenem against the E. coli Tg1 (NDM-1) strain. The most promising compound 3a demonstrated potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE strains with FICI as low as 0.09. Moreover, its IC50 value and inhibition mechanism were also confirmed by using the enzyme inhibition assay and the ESI-MS analysis respectively. Importantly, compound 3a has acceptable toxicity and is not a PAINS. Because of its structural simplicity and potent synergistic activity in combination with meropenem, we propose that compound 3a may be a promising meropenem adjuvant and a new series of such compounds may worth further investigations.
- Jin, Wen Bin,Xu, Chen,Cheung, Qipeng,Gao, Wei,Zeng, Ping,Liu, Jun,Chan, Edward W.C.,Leung, Yun-Chung,Chan, Tak Hang,Wong, Kwok-Yin,Chen, Sheng,Chan, Kin-Fai
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- 1,2-BENZISOSELENAZOL-3(2H)-ONE AND 1,2-BENZISOTHIAZOL-3(2H)-ONE DERIVATIVES AS BETA-LACTAM ANTIBIOTIC ADJUVANTS
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Provided herein are compositions and methods useful in the treatment of beta-lactam antibiotic resistant bacteria.
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Paragraph 0341; 0342
(2019/10/04)
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- 3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells
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A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1–5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50of 50–250?nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket.
- Eurtivong, Chatchakorn,Semenov, Victor,Semenova, Marina,Konyushkin, Leonid,Atamanenko, Olga,Reynisson, Jóhannes,Kiselyov, Alex
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p. 658 - 664
(2016/12/27)
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- Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation
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Targeting thymidylate kinase (TMPK) that catalyzes the phosphotransfer reaction for formation of dTDP from dTMP is a new strategy for anticancer treatment. This study is to understand the inhibitory mechanism of a previously identified human TMPK (hTMPK) inhibitor YMU1 (1a) by molecular docking, isothermal titration calorimetry, and photoaffinity labeling. The molecular dynamics simulation suggests that 1a prefers binding at the catalytic site of hTMPK, whereas the hTMPK inhibitors that bear pyridino[d]isothiazolone or benzo[d]isothiazolone core structure in lieu of the dimethylpyridine-fused isothiazolone moiety in 1a can have access to both the ATP-binding and catalytic sites. The binding sites of hTMPK inhibitors were validated by photoaffinity labeling and mass spectrometric studies. Taking together, 1a and its analogues stabilize the conformation of ligand-induced degradation (LID) region of hTMPK and block the catalytic site or ATP-binding site, thus attenuating the ATP binding-induced closed conformation that is required for phosphorylation of dTMP.
- Chen, Yi-Hsuan,Hsu, Hua-Yi,Yeh, Ming-Tyng,Chen, Chen-Cheng,Huang, Chang-Yu,Chung, Ying-Hsuan,Chang, Zee-Fen,Kuo, Wei-Chen,Chan, Nei-Li,Weng, Jui-Hsia,Chung, Bon-Chu,Chen, Yu-Ju,Jian, Cheng-Bang,Shen, Ching-Chieh,Tai, Hwan-Ching,Sheu, Sheh-Yi,Fang, Jim-Min
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p. 9906 - 9918
(2016/11/19)
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- LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS
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Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with one or more of the lysophosphatidic acid receptors are provided.
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Paragraph 1134; 1136
(2014/07/23)
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- Thieno[2,3-b]pyridines as negative allosteric modulators of metabotropic GluR5 receptors: Hit-to-lead optimization
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An HTS campaign of our corporate compound library resulted in thieno[2,3-b]pyridines derivative hits with mGluR5 negative allosteric modulator effects. During the hit-to-lead development our objective was to improve affinity, and to keep the ligand efficiency values at an acceptable level. After different modifications of the linker resulted in a 2-sulfonyl-thieno[2,3-b] pyridines derivative, which fulfilled the lead criteria.
- Nógrádi, Katalin,Wágner, Gábor,Domány, Gy?rgy,Bobok, Amrita,Magdó, Ildikó,Kiss, Béla,Kolok, Sándor,Fónagy, Katalin,Gyertyán, István,Háda, Viktor,Kóti, János,Gál, Krisztina,Farkas, Sándor,Keseru, Gy?rgy M.,Greiner, István,Szombathelyi, Zsolt
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p. 3845 - 3849
(2014/09/03)
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- Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d] pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors
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A useful and rapid access to libraries of N-arylbenzo[b]thieno[3,2-d] pyrimidin-4-amines and their pyrido and pyrazino analogues was designed and optimized for the first time via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with N′-(2-cyanoaryl)-N,N- dimethylformimidamides obtained by reaction of thiophene precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. N-arylpyrido[3′,2′:4,5]thieno[3,2-d] pyrimidin-4-amine series of compounds (4a-j) turned out to be particularly promising for the development of new pharmacological inhibitors of CK1 and CLK1 kinases.
- Loidreau, Yvonnick,Marchand, Pascal,Dubouilh-Benard, Carole,Nourrisson, Marie-Renée,Duflos, Muriel,Lozach, Olivier,Loa?c, Nadège,Meijer, Laurent,Besson, Thierry
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p. 171 - 183
(2013/02/22)
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- Synthesis and evaluation of pyrido-thieno-pyrimidines as potent and selective Cdc7 kinase inhibitors
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Cdc7 kinase plays a critical role in the regulation of DNA replication in eukaryotic cells and has been proposed as a target for cancer therapy. We have identified a class of Cdc7/Dbf4 inhibitors with a pyrido-thieno-pyrimidine core structure. Synthesis o
- Zhao, Chunlin,Tovar, Christian,Yin, Xuefeng,Xu, Qui,Todorov, Ivan T.,Vassilev, Lyubomir T.,Chen, Li
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scheme or table
p. 319 - 323
(2011/02/26)
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- BENZISOTHIAZOLES USEFUL FOR TREATING OR PREVENTING HCV INFECTION
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The present invention relates to benzisothiazoles and pharmaceutical compositions thereof that inhibit replication and/or proliferation of HCV virus. The present invention also relates to the use of the benzisothiazoles and pharmaceutical compositions comprising the compounds to treat or prevent HCV infections.
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Page/Page column 150-151; 152-153
(2010/11/23)
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- Deoxydative Thiation of 3-Substituted Pyridine N-Oxides with 4-Methoxytoluene-α-thiol: A Divergent Route to Pyridinethiols
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Synthesis of 3-substituted 2-pyridinethiols was achieved by thiation of pyridine N-oxides with 4-methoxytoluene-α-thiol in the presence of diethylcarbamoyl chloride followed by cleavage of the resulting sulfides.The case of substitution was shown to be affected by nucleophilicity of the N-oxide oxygen.Addition of zinc bromide to the reaction, a need for triethylamine, decreased most of the yield for thiation products but the formation of 3-methoxy-2-methoxybenzylthiopyridine was only improved.A plausible mechanism of the substitution, particularly β-thiation to the N-oxide function, is discussed compared with the regiochemistry observed in the reaction with diethoxyphosphoryl chloride instead of diethylcarbamoyl chloride.The debenzylation to pyridinethiol was also found to be dependent on the electron-density in the pyridine ring.
- Sato, Nobuhiro,Nagano, Eiichi
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p. 691 - 698
(2007/10/02)
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- Nucleophilic Displacements in Pyridine Rings
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The reactions of halopyridines containing an electron withdrawing group (-CN, -CO2R, -COMe, -NO2) with sulphur nucleophiles is reported.
- Dunn, A. D.,Norrie, R.
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- Pyridinethiones. IX Preparation of Ricinidine, Thioricinidine and Other 2(1H)-Pyridones and -thiones Related to Nicotinic acid
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1(1H)-Pyridones and -thiones related to 1-substituted nicotinic acid derivatives have been prepared via the corresponding 1-substituted-3-formyl-2(1H)-pyridones and -thiones.A number of synthetic procedures for the interconversion of functional groups in these nicotinic acid derivatives are given i.e. preparation of the aldoximes, nitriles, carboxamides and carboxylic acids as well as the 3-hydroxyalkyl derivatives.The course of the basic peroxide oxidation of the 1-substituted-3-formyl-2(1H)-pyridinethiones is found to be very dependent upon the electronegativity ofthe 1-substituent.A preparation of ricinidine is also described.
- Becher, Jan,Johansen, Tea,Michael, Maged Aziz
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