- Utility of bis(methylthio)methylene malononitrile as a synthon in the synthesis of new poly-functionalized cyanoiminopyrimidines
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Abstract: A new series of 4-(alkyl/arylamino)-6-amino-5-cyano-2-cyanoimino-1H-pyrimidine was obtained via one-pot three-component reaction of bis(methylthio)methylene malononitrile, primary amines, and cyanoguanidine using sodium ethoxide as basic catalys
- Moustafa, Amr Hassan,Amer, Amer Anwar
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- One-Pot Synthesis and Antiproliferative Activity of Highly Functionalized Pyrazole Derivatives
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A series of highly functionalized pyrazole derivatives has been prepared by a one-pot, versatile and regioselective procedure. Pyrazoles 1–29 were tested in cell-based assay to assess their antiproliferative activity against a panel of tumour cells. Addit
- Iervasi, Erika,Lusardi, Matteo,Ponassi, Marco,Rosano, Camillo,Rotolo, Chiara,Spallarossa, Andrea
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- Triflic acid-mediated N-heteroannulation of β-anilino-β-(methylthio)acrylonitriles: a facile synthesis of 4-amino-2-(methylthio)quinolines
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Various functionalised 4-amino-2-(methylthio)quinolines are synthesised through triflic acid-mediated N-heteroannulation of α-functionalized-β-anilino-β-(methylthio)acrylonitriles for the first time. The N-heteroannulation process is highly chemoselective and has mild reaction conditions. However, this process fails in the absence of the β-methylthio group in the acrylonitriles. In addition, a new double N-heteroannulation process is demonstrated to synthesise indolo[3,2-c]quinolines from non-heterocyclic precursors. Natural product isocryptolepine is synthesised in four steps from an acyclic precursor.
- Bandyopadhyay, Debashruti,Panigrahi, Adyasha,Peruncheralathan, S.,Radhakrishnan, Divya,Thirupathi, Annaram
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supporting information
p. 8544 - 8553
(2021/10/20)
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- Design, Synthesis, biological Evaluation, and molecular docking studies of novel Pyrazolo[3,4-d]Pyrimidine derivative scaffolds as potent EGFR inhibitors and cell apoptosis inducers
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A series of novel hybrid pyrazolo[3,4-d]pyramidine derivatives was designed and chemically synthesized in useful yields. The synthesized compounds were structurally characterized by the usual techniques. All the new synthesized compounds were biologically screened in vitro for their antiproliferative activities against a panel of four cancer cell lines, namely HepG-2, MCF-7, HCT-116, and Hela. The results of cytotoxic evaluation indicated that compound 14d was appeared to be the most prominent broad-spectrum cytotoxic activity and significantly more potent than sorafenib with IC50 values of 4.28, 5.18, 3.97, and 9.85 μM against four cell lines (HePG2, Hela, HCT-116 and MCF-7). In addition, compound 15 was displayed promising antiproliferative effect against all tested cell lines with IC50 value less than 11 μM compared with sorafenib as a control drug. Besides, structurally pharmacophoric features indicated that pyrazolo[3,4-d]pyrimidine scaffold having an amide linker and substituted with phenyl moiety at the 5-position was more potent than those possessing azomethine methyl, azomethine proton and carbomethene linkers, which lead to significant decrease in antiproliferative activity. The most potent compounds were further selected and evaluated for their activities against epidermal growth factor receptor (EGFR) kinase inhibitors according to homogenous time resolved fluorescence (HTRF) assay. The most potent compound 14d exhibited the most promising inhibitory activity against EGFRWT with IC50 value of 56.02 ± 1.38 μM compared with gefitinib as control drug with IC50 value of 41.79 ± 1.07 μM. Moreover, the inhibition of cell cycle progression and induction of apoptosis in the A549 cell line at G2/M and pre-G1 phases of cell cycle might contribute to cancer treatment that evaluated by Annexin V-FITC/PI double staining detection method. Finally, molecular docking studies were conducted to investigate that probable binding conformations of these anticancer agents and ADME properties were calculated to predict pharmacokinetics and toxic properties of the target compounds.
- Bayoumi, Ashraf H.,El-Morsy, Ahmed M.,Hagras, Mohamed,Sherbiny, Farag F.,Sobhy, Mohamed
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- From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes
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Kinetics of the reactions of isocyanates, isothiocyanates, carbodiimides, carbon disulfide, and carbon dioxide with carbanions or enamines (reference nucleophiles) have been measured photometrically in acetonitrile or DMSO solution at 20 °C. The resulting second-order rate constants and the previously published reactivity parameters N and sN of the reference nucleophiles were substituted into the correlation log k2(20 °C) = sN(N + E) to determine the electrophilicity parameters of the heteroallenes: TsNCO (E = -7.69) ? PhNCO (E = -15.38) > CS2 (E = -17.70) ≈ PhNCS (E = -18.15) > PhNCNPh (E = -20.14) ? CyNCNCy (E ≈ -30). An approximate value could be derived for CO2 (-16 E - 11). Quantum chemical calculations were performed at the IEFPCM(DMSO)/B3LYP-D3/6-311+G(d,p) level of theory and compared with experimental Gibbs activation energies. The distortion-interaction model was used to rationalize the different reactivities of O- and S-substituted heteroallenes. Eventually it is demonstrated that the electrophilicity parameters determined in this work can be used as ordering principle for literature-known reactions of heteroallenes.
- Li, Zhen,Mayer, Robert J.,Ofial, Armin R.,Mayr, Herbert
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supporting information
p. 8383 - 8402
(2020/05/22)
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- Application of malononitrile compound as bactericide
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The invention discloses an application of a malononitrile compound represented by a general formula I as a bactericide, wherein substituents in the formula are defined in the specification. The compound represented by the general formula I has excellent a
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Paragraph 0296
(2020/08/18)
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- Design, synthesis and biological evaluation of certain CDK2 inhibitors based on pyrazole and pyrazolo[1,5-a] pyrimidine scaffold with apoptotic activity
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Different series of novel pyrazole and pyrazolo[1,5-a] pyrimidine derivatives (2a-g), (3a-c), (7a-d) and (10a-e) were designed, synthesized and evaluated for their ability to inhibit CDK2/cyclin A2 enzyme in vitro. In addition, the cytotoxicity of the newly synthesized compounds was screened against four different human cancer cell lines. The CDK2/cyclin A2 enzyme inhibitory activity revealed that compounds (2d) and (2 g) are among the most active with inhibitory activity values of 60% and 40%, respectively, while compounds (7d) and (10b) exhibited the highest activity among the newly synthesized derivatives against four tumor cell lines (HepG2, MCF-7, A549 and Caco2) with IC50 values 24.24, 14.12, 30.03 and 29.27 μM and 17.12, 10.05, 29.95 and 25.24 μM, respectively. Flow cytometry cell cycle assay was carried for compounds (7d) and (10b) to investigate their apoptotic activity. The obtained results revealed that they induced cell-cycle arrest in the G0-G1phase and reinforced apoptotic DNA fragmentation. Molecular modeling studies have been carried out to gain further understanding the binding mode of the target compounds together with field alignment to define the similar field properties.
- Ali, Ghada M.E.,Ibrahim, Diaa A.,Elmetwali, Amira M.,Ismail, Nasser S.M.
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- S-glycosides in medicinal chemistry: Novel synthesis of cyanoethylene thioglycosides and their pyrazole derivatives
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A one-pot reaction of a sodium 2-cyanoethylene-1-thiolate salt with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides affords a new class of cyanoethylene thioglycosides. The conversion to the corresponding 5-aminopyrazoles confirms the E-co
- Elgemeie, Galal,Fathy, Nahed,Zaghary, Wafaa,Farag, Ayman
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p. 198 - 212
(2017/02/15)
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- TRICYCLIC PIPERAZINE DERIVATIVE
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Disclosed are compounds useful as inhibitors of Phosphodiesterase 1 (PDE1), compositions thereof, and methods of using the same.
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Paragraph 0503
(2016/04/19)
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- Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses
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There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing. Curing the common cold! A cluster of pyrazolopyrimidines with potent broad-spectrum activity against enteroviruses was discovered. Extensive structure-property relationship analyses led to the identification of 3-(4-trifluoromethyl-phenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine, shown to be a blocker of the viral capsid protein, as a lead compound for drug development with favorable physicochemical, pharmacokinetic, and toxicological properties.
- Makarov, Vadim A.,Braun, Heike,Richter, Martina,Riabova, Olga B.,Kirchmair, Johannes,Kazakova, Elena S.,Seidel, Nora,Wutzler, Peter,Schmidtke, Michaela
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supporting information
p. 1629 - 1634
(2015/10/06)
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- A one-pot, three-component aminotriazine annulation onto 5-aminopyrazole-4-carbonitriles under microwave irradiation
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A one-pot, three-component, microwave-assisted reaction of 5-aminopyrazole-4-carbonitriles, triethyl orthoformate and cyanamide afforded novel 7-arylamino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazine-8-carbonitriles. The reaction proceeded in a chemo- and regioselective manner resulting in the successful amino-1,3,5-triazine annulation onto 5-aminopyrazole-4-carbonitriles to give 4-aminopyrazolo[1,5-a][1,3,5]triazine-8-carbonitriles. The operational simplicity of the method and high purity of the products, which can be isolated via simple filtration, make this approach attractive for the preparation of a library of compounds for drug discovery processes.
- Lim, Felicia Phei Lin,Luna, Giuseppe,Dolzhenko, Anton V.
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p. 521 - 524
(2015/02/19)
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- A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile derivatives
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New 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitriles are synthesized in good yields, via cyclocondensation of 5-amino-1-(2-oxo-2-arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles, which are prepared by the reaction of 5-amino-3-arylamino-
- Khalafy, Jabbar,Poursattar Marjani, Ahmad,Salami, Fatemeh
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p. 6671 - 6674
(2014/12/11)
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- 3,5-DIAMINOPYRAZOLE KINASE INHIBITORS
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Provided herein are 3,5-diaminopyrazoles, for example, compounds of Formula IA, that are useful for modulating regulated-in-COPD kinase activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventi
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Paragraph 00290
(2013/09/26)
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- Synthesis of novel bis-thiadiazoles, bis-triazoles and polypyrazole derivatives based on hydrazonoyl halides
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A series of novel bis-thiadiazoles and bis-triazoles derivatives were synthesized via the reaction of hydrazonoyl halides with different moieties. Also, the synthesis and mechanism for polypyrazole formation are described via reaction of bis-hydrazonoyl w
- Sayed, Abdelwahed R.
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p. 5293 - 5298
(2013/07/05)
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- One-pot synthesis of functionalized tetrahydro-1,4-thiazepines
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One-pot synthesis of (5Z,7Z)-5-amino-7-(ethyl or arylimino)-2,3,4,7- tetrahydro-1,4-thiazepine-6-carbonitriles from cyclocondensation of 2-((ethyl or arylamino)(mercapto)methylene)malononitrile potassium salts or their methylated derivatives with 2-chloro
- Bakavoli,Beyzaei,Rahimizadeh,Eshghi
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experimental part
p. 1181 - 1185
(2011/05/06)
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- MODULATION OF PROTEIN TRAFFICKING
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Compounds and compositions are provided for treatment or amelioration of one or more disorders characterized by defects in protein trafficking. A method of treating a disorder characterized by impaired protein trafficking includes administering to a subject or contacting a cell with a compound of Formula I: [formula here] or pharmaceutically acceptable salts or derivatives thereof.
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Page/Page column 205
(2009/06/27)
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- One-pot synthesis of 6-substituted amino-2,4-diaminopyrimidine derivatives using ketene dithioacetals with amines and guanidine carbonate
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6-Substituted amino-2,4-diaminopyrimidine derivatives were prepared by one-pot synthesis using ketene dithioacetals, amine compounds, and guanidine carbonate in pyridine. These pyrimidine products displayed blue fluorescence in the solid state.
- Hirosa, Miki,Hagimori, Masayori,Shigemitsu, Yasuhiro,Mizuyama, Naoko,Wang, Bo-Cheng,Tominaga, Yoshinori
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p. 899 - 903
(2009/09/29)
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- Discovery of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke
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We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino) pyrazolo-[1,5-a]pyrimidine-3-carboxamide 7o and
- Mukaiyama, Harunobu,Nishimura, Toshihiro,Shiohara, Hiroaki,Kobayashi, Satoko,Komatsu, Yoshimitsu,Kikuchi, Shinji,Tsuji, Eiichi,Kamada, Noboru,Ohnota, Hideki,Kusama, Hiroshi
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p. 881 - 889
(2008/02/08)
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- Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-acetals
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Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene compounds. The priority of the formation of the thiophene or pyrrole ring is investigated.
- Sommen, Geoffroy,Comel, Alain,Kirsch, Gilbert
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p. 1557 - 1564
(2007/10/03)
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- Synthesis and antiproliferative activity of basic thioanalogues of merbarone
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Three series of 5-substituted 1,3-diphenyl-6-(ω-dialkyl- and ω-cyclo-aminoalkyl)thio-2-thiobarbiturates (11-13) were synthesized as polysubstituted thioanalogues of merbarone, a topoisomerase II inhibitor acting on the catalytic site. To better understand pharmacophore requirements, a forth series of conformationally constrained analogues 14 was also prepared. Derivatives 11b,e, 14b,e,h,i,j were active in the low micromolar concentration range (IC50: 3.3-4.3 μM), whereas compounds 11a,c,d,f,h,j and 13a,b,d,g,j and 14a,d,f showed IC50 values between 10 and 15.5 μM. In constrast, compounds 12a-c,g-j, 13e,f,h and 14k were inactive. Cytotoxicity data provided from N.C.I. on selected compounds provided evidence that 11b,d, 13d,g and 14b,d,f,h,i,j were endowed with potent antiproliferative activity against leukemia and prostate cell lines (GI50 up to 0.01 μM). In general, bicyclic derivatives 14 were up to 10-fold more potent than monocyclic counterparts against solid tumor-derived cell lines. SAR studies indicated that, in general, a certain tolerability in length of the alkyl side chains and in shape of distal amines is allowed in the four series, but in the monocyclic derivatives (11-13) antiproliferative activity was strongly affected by the nature of the 5-substituents (COOC2H5>COCH3?C6H 5). Compounds 11b and 14b were also evaluated against KB cell subclones expressing altered levels of topoisomerases or the multidrug resistance phenotype (MDR). In both cases the above compounds showed a decrease in potency. In enzyme assays, 11b and 14b turned out to be inhibitors of topoisonerase II as merbaron.
- Ranise, Angelo,Spallarossa, Andrea,Schenone, Silvia,Bruno, Olga,Bondavalli, Francesco,Pani, Alessandra,Marongiu, Maria Elena,Mascia, Valeria,La Colla, Paolo,Loddo, Roberta
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p. 2575 - 2589
(2007/10/03)
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- An improved method for the synthesis of aminothiophenes precursors of thieno[2,3-b]pyrrole
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Thiophenes 2 can easily be synthesized in two steps by using phenyl isothiocyanate and activated methylene compounds.
- Sommen, Geoffroy,Comel, Alain,Kirsch, Gilbert
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p. 257 - 259
(2007/10/03)
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- Linear ketenimines. Variable structures of C,C-Dicyanoketenimines and C,C-Bis-sulfonylketenimines
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C,C-Dicyanoketenimines 10a-c were generated by flash vacuum thermolysis of ketene N,S-acetals 9a-c or by thermal or photochemical decomposition of α-azido-β-cyanocinnamonitrile 11. In the latter reaction, 3,3-dicyano-2-phenyl-1-azirine 12 is also formed. IR spectroscopy of the keteniminines isolated in Ar matrixes or as neat films, NMR spectroscopy of 10c, and theoretical calculations (B3LYP/6-31G*) demonstrate that these ketenimines have variable geometry, being essentially linear along the CCN-R framework in polar media (neat films and solution), but in the gas phase or Ar matrix they are bent, as is usual for ketenimines. Experiments and calculations agree that a single CN substituent as in 13 is not enough to enforce linearity, and sulfonyl groups are less effective that cyano groups in causing linearity. C,C-Bis(methylsulfonyl)ketenimines 4-5 and a C-cyano-C-(methylsulfonyl)ketenimine 15 are not linear. The compound p-O2NC6H4N=C=C(COOMe)2 previously reported in the literature is probably somewhat linearized along the CCNR moiety. A computational survey (B3LYP/6-31G*) of the inversion barrier at nitrogen indicates that electronegative C-substituents dramatically lower the barrier; this is also true of N-acyl substituents. Increasing polarity causes lower barriers. Although N-alkylbis(methylsulfonyl)ketenimines are not calculated to be linear, the barriers are so low that crystal lattice forces can induce planarity in N-methylbis(methylsulfonyl)ketenimine 3.
- Finnerty, Justin,Mitschke, Ullrich,Wentrup, Curt
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p. 1084 - 1092
(2007/10/03)
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- Synthesis and antimalarial activity of substituted pyrazole derivatives
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The development of new antimalarial drugs is an urgent priority considering the increasing prevalence of drug-resistant Plasmodium falciparum parasites. A series of pyrazoles are described as part of efforts directed toward the synthesis of some potent an
- Dominguez, Jose N.,Charris, Jaime E.,Caparelli, Mario,Riggione, Flavia
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p. 482 - 488
(2007/10/03)
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- A facile method for the synthesis of novel pyridinone derivatives via ketene N,S-acetals
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A simple and easy method is provided for the synthesis of the novel pyridinone derivatives (3a-e), (8a-c) and (10a-c) by the reaction of ketene acetals (2a-e), (7a-c) and (9a-c) with ethyl cyanoacetate respectively. Compounds (3b-d) reacted with triethyl
- Al-Afaleq
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p. 3557 - 3567
(2007/10/03)
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- Diaminomethylidene derivatives
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Novel diaminomethylidene derivatives represented by formula (I) STR1 wherein R1 is a hydrogen atom, a C1 -C6 alkyl group, a C3 -C6 cycloalkyl group and others, R2 is a group of the followin
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- Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(Phenylamino)pyrazolo[3,4-d]pyrimidines
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In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP- competitive inhibitors interacting w
- Traxler, Peter,Bold, Guido,Frei, Joerg,Lang, Marc,Lydon, Nicholas,Mett, Helmut,Buchdunger, Elisabeth,Meyer, Thomas,Mueller, Marcel,Furet, Pascal
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p. 3601 - 3616
(2007/10/03)
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- Heteroatom Rearrangements. S,N, O,N, and N,N Double Rearrangements. X-Ray Molecular Structure of 5-Cyano-6-methylthio-2,3-diphenyl-pyrimidin-4(3H)-one
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New heteroatom rearrengements are reported; 'S,N, O,N, and N,N double rearrangements' take place when acrylonitriles, substituted at C-3 by two heteroatom groups (MeS or MeSe, and SH, OH, or NHPh), condense with aromatic carboxylic acids in the presence o
- Yokoyama, Masataka,Hatanaka, Hidekatsu,Sasaki, Atsuhi,Shiraishi, Tadashi,Kumata, Katsushi,et al.
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p. 1187 - 1196
(2007/10/02)
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- SYNTHESIS OF THIENOPYRIDINES
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Several thienopyridines could be easily synthesized by methallation using LDA directly from 3-(disubstituted amino)-2-cyano-3-methylthioacrylonitriles.
- Yokoyama, Masataka,Tohnishi, Masanori,Kurihara, Akemi,Imamoto, Tsuneo
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p. 1933 - 1936
(2007/10/02)
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- DIAMINOTHIAZOLES AND DIAMINOTHIOPHENES
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Several 2,4-diaminothiazoles and 2,4-diaminothiophenes could be easily obtained by metallation using LDA from aminomethylthiomethylenecyanamides 2 and aminomethylthiomethylenemalononitrile, respectively.
- Yokoyama, Masataka,Kurauchi, Masahiko,Imamoto,Tsuneo
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p. 2285 - 2288
(2007/10/02)
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