- Novel pyrimidine derivatives as potential anticancer agents: Synthesis, biological evaluation and molecular docking study
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In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitu-mor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking.
- Tylińska, Beata,Wiatrak, Benita,Czy?nikowska, ?aneta,Cie?la-Niechwiadowicz, Aneta,G?barowska, El?bieta,Janicka-K?os, Anna
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Read Online
- Antioxidant and antimicrobial properties of nickel(II), cobalt(III), and zinc(II) complexes of a Schiff base ligand
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A series of mononuclear Ni(II), Co(III), and Zn(II) complexes based on a Schiff base ligand, 4-chloro-6-[2-(pyrazin-2-ylmethylene)hydrazinyl]pyrimidine (HL), have been synthesized and characterized by physicochemical and spectroscopic methods. The complexes were found to have superior radical scavenging potency against DPPH, superoxide anion, hydroxyl, and ABTS radicals than free HL. The antibacterial effects of the complexes against Gram-positive and Gram-negative bacteria were also higher than that of free HL.
- Hasi, Qi-Meige,Fan, Yan,Feng, Xiao-Xia,Yao, Xiao-Qiang,Liu, Jia-Cheng
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Read Online
- In silico and in vitro Antitubercular Studies for Nitrogen Rich Hybrids of homopiperazine-pyrimidine-Pyrazole Adducts
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Novel homopiperazine-pyrimidine-pyrazole hybrids (3a-j) were synthesized using ethyl 2-cyanoacetate and 4,6-dichloropyrimidine as starting materials by a multi-step process to afford ethyl 5-amino-1-(6-chloropyrimidin-4-yl)-1H-pyrazole-4-carboxylate in good yields using polar protic media. The intermediate 1, in two steps, chloroamine condensation followed by acid amine coupling, furnished the title compounds ethyl 5-amino-1-(6-(4-substituted aryl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate (3a-j). The synthesized compounds were docked in the crystal structure of Mycobacterium tuberculosis (PDB ID: 4TRO) to get insights into structural requirements for antitubercular activity. In vitro antitubercular activity against M. tuberculosis H37Rv strains showed that compounds 3a, 3d, 3e and 3g were found to be the most potent (Docking score: > -21; MIC = 1.6 μg/mL) among the synthesized molecules. All the synthesized compounds showed acceptable drug-like properties which make them suitable for further lead modification using in silico design approaches.
- Marvaniya, Vanita,Pansuriya, Vrajlal,Patel, Popatbhai,Patel, Shivani,Vavaiya, Bhavinkumar
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p. 562 - 568
(2022/02/22)
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- ErbB RECEPTOR INHIBITORS AS ANTI-TUMOR AGENTS
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Provided herein are novel compounds as inhibitors of type I receptor tyrosine kinases, the pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and the use of the compounds and salts thereof in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans.
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Page/Page column 132; 133
(2021/09/17)
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- GPR52 MODULATOR COMPOUNDS
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The disclosures herein relate to novel compounds of Formula (1): (1) and salts thereof, wherein R1, Q, X, Y and Z are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with GPR52 receptors.
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Paragraph 73-74
(2021/05/15)
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- QUINAZOLINE DERIVATIVES AS ANTITUMOR AGENTS
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The present application relates to novel quinazoline compounds as inhibitors of type I receptor tyrosine kinases, the pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and the use of the compounds and salts thereof in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans.
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Page/Page column 95-96
(2020/04/25)
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- Pyrimidine hydrazone derivative and preparation method and application thereof
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The invention relates to pyrimidine hydrazone derivatives as shown in a chemical structural formula I or II, pharmaceutically acceptable salts and pharmaceutical compositions thereof, and an application of the pyrimidine hydrazone derivatives and the pharmaceutically acceptable salts and the pharmaceutical compositions in preparation of influenza virus neuraminidase inhibitors, wherein X is selected from: fluorine, chlorine, bromine, hydroxyl, dihydroxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-C1-C2 alkoxy, 2-hydroxy-6-C1-C2 alkoxy, 3-hydroxy-2-C1-C2 alkoxy, 3-hydroxy-4-C1-C2 alkoxy, 3-hydroxy-5-methyl C1-C2 alkoxy , 3-hydroxy-6-C1-C2 alkoxy, 4-hydroxy-2-C1-C2 alkoxy, 4-hydroxy-3-C1-C2 alkoxy, 4-hydroxy-3, 5-diC1-C2 alkoxy, trihydroxy or 4-hydroxy-3,5-dimethyl; and Y is selected from: fluorine, chlorine, bromine, acetamido, hydroxyl or methoxy.
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Paragraph 0036-0037; 0044-0046
(2020/11/23)
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- Design, synthesis, and anticancer evaluation of acetamide and hydrazine analogues of pyrimidine
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A library of acetamide and hydrazine analogues were generated on the pyrimidine ring through a multistep reaction starting from 5-nitro-pyrimidine-4,6-diol and pyrimidine-4,6-diol, respectively. The synthesized analogues were screened for in vitro cytotoxic activity against various human cancer cell lines like HCT-1 and HT-15 (colon), MCF-7(breast), PC-3 (prostrate), SF268 (CNS) using MTT method. From the bioassay results, it was observed that even though many of the synthesized derivatives exhibited a good potency against various screened cancer cell lines, compound 14a from the acetamide series was found to show potent anticancer activity on all the tested cancer cell lines with IC50 value of 0.36μM on CNS cell line and 1.6μM on HT-21 cell line, and compound 19xxi from hydrazine series of pyrimidine showed potent activity against three tested cancer cell lines with IC50 value of 0.76μM on HT-29 cell line, 2.6μM on HCT-15, and 3.2μM on MCF-7 cell line.
- Chashoo, Gousia,Khazir, Jabeena,Maqbool, Tariq,Mir, Bilal Ahmad,Pilcher, Lynne,Riley, Darren
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- New crystal forms of dihydropyrazolone compound and preparation method of new crystal form
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The invention relates to new crystal forms of a dihydropyrazolone compound and a preparation method of the new crystal form. Specifically, the invention relates to a crystal form A and a crystal formB of 1-(6-(2-oxa-8-azaspiro [4.5] decane-8-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-1H-pyrazole-3-sodium phenolate. The preparation method comprises the following steps: preparing 2-(6-(2-oxa-8-azaspiro [4.5] decane-8-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-3H-pyrazole-3-one into a sodium salt in an organic solvent, and crystallizing, thereby obtainingthe product. The new crystal forms of the dihydropyrazolone compound can be used to prevent and/or treat diseases associated with PHD activity.
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Paragraph 0082-0084; 0089; 0090
(2020/11/05)
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- New crystal forms of PHD inhibitor and preparation method thereof
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The invention relates to new crystal forms of a PHD inhibitor and a preparation method of the new crystal forms. Specifically, the invention relates to a crystal form A and a crystal form B of 1-(6-(7-oxa-2-azaspiro [3.5] non-2-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-3H-pyrazole-3-sodium phenolate. The preparation method comprises the following steps: preparing 2-(6-(7-oxa-2-azaspiro [3.5] non-2-yl) pyrimidine-4-yl)-4-(1H-1, 2, 3-triazole-1-yl)-1, 2-dihydro-3H-pyrazole-3-one into a sodium salt in an organic solvent, and crystallizing, thereby obtaining the product. It can be used to prevent and/or treat diseases associated with PHD activity.
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Paragraph 0077-0079; 0084; 0085
(2020/11/05)
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- Novel N-thioamide analogues of pyrazolylpyrimidine based piperazine: Design, synthesis, characterization, in-silico molecular docking study and biological evaluation
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Utilizing molecular hybridization approach, a progression of novel pyrazolylpyrimidine based N-thioamide derivatives of piperazine were identified in an effort to develop newer antibacterial and antitubercular agents against the cumulative bacterial resistance. Spectral analysis using Mass, 1H NMR and 13C NMR spectral techniques have been studied in order to affirm the structure of synthesized end molecules. Biological evaluation of all synthesized molecules were studied in-vitro for their antibacterial, antituberculosis and antimalarial efficacy against various bacterial and fungal strains, H37Rv and Plasmodium falciparum respectively. Molecular docking and ADME properties prediction study were also carried out for better insights of responsible proteins with the synthesized molecules. Interestingly, some of the pyrazolylpyrimidine based piperazine N-thioamide derivatives exhibited potential antibacterial, antifungal and antimalarial potency.
- Vekariya, Mayur K.,Patel, Dhaval B.,Pandya, Pranav A.,Vekariya, Rajesh H.,Shah, Prapti U.,Rajani, Dhanji P.,Shah, Nisha K.
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p. 551 - 565
(2018/09/18)
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- Dihydropyrazolone compound as well as preparation method and medical application thereof
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The invention relates to a dihydropyrazolone compound as well as a preparation method and medical application thereof, in particularly relates to a general formula (I) compound shown in the specification, as well as a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a proline hydroxylase (PHD) inhibitor, the compound and the pharmaceutical composition containing the compound can be used in treating and/or preventing of PHD -activity- related diseases such as cardiovascular diseases, chronic kidney disease, anemia, wounds, cancer, autoimmune diseases and the like. In the general formula (I), the definition of each substituent in the formula is the same as that in the specification.
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Paragraph 0170; 0173-0174; 0179-0180
(2019/05/15)
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- Pyrimidine-based pyrazoles as cyclin-dependent kinase 2 inhibitors: Design, synthesis, and biological evaluation
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A series of new pyrimidine-pyrazole hybrid molecules were designed as inhibitors of cyclin-dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2-CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC50??20?nm); which can be further optimized to have selectivity over other kinase isoforms.
- Vekariya, Mayur K.,Vekariya, Rajesh H.,Brahmkshatriya, Pathik S.,Shah, Nisha K.
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p. 1683 - 1691
(2018/09/10)
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- Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia
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Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure–activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.
- Beck, Hartmut,Jeske, Mario,Thede, Kai,Stoll, Friederike,Flamme, Ingo,Akbaba, Metin,Ergüden, Jens-Kerim,Karig, Gunter,Keldenich, J?rg,Oehme, Felix,Militzer, Hans-Christian,Hartung, Ingo V.,Thuss, Uwe
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supporting information
p. 988 - 1003
(2018/04/19)
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- Synthesis, biological activities and molecular docking simulation of hydrazone scaffolds of carvacrol, thymol and eugenol
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In present work, we report the synthesis of 12 new hydrazones and sulfonyl hydrazones linkage containing carvacrol, thymol and eugenol derivatives by simple condensation reactions. Synthesized derivatives have been characterized by 1H NMR, 13C NMR, LC–MS, and X-ray single crystallography techniques, and these derivatives were screened for anticancer testing by using sulforhodamine B assay and anti-oxidant testing by using DPPH assay. Docking studies of all the derivatives against the active site of human heme oxygenase-1 indicated that interaction with the maximum site of the amino acid residue of human heme oxygenase-1 was crucial for anti-oxidant activity. The results show that all derivatives possess interesting biological activities.
- Rajput, Jamatsing D.,Bagul, Suresh D.,Bendre, Ratnamala S.
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p. 6601 - 6616
(2017/10/05)
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- Synthesis of 8-Bromo-7-chloro[1,2,4]triazolo[4,3- C ]pyrimidines, Their Ring Rearrangement to [1,5- C ] Analogues, and Further Diversification
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8-Bromo-7-chloro[1,2,4]triazolo[4,3-c]pyrimidines were prepared by bromine-mediated oxidative cyclization of the aldehyde-derived hydrazones. The structure of one such product was unambiguously confirmed by single-crystal X-ray analysis. While the C-5 unsubstituted 1,2,4-triazolo[4,3-c]pyrimidine chemotype is extremely susceptible to ring isomerization at ambient conditions, the C-5-substituted analogues were found to be quite stable, permitting isolation in pure form. Nevertheless, they can still be converted into the 1,2,4-triazolo[1,5-c]pyrimidines by base- or acid-promoted Dimroth rearrangement. The presence of halogen functionalities on the pyrimidine nucleus renders the products useful as versatile synthetic intermediates for the easy diversification, as evidenced by palladium-catalyzed Kumada cross-couplings and Buchwald-Hartwig amination, as well as direct aromatic substitution.
- Tang, Caifei,Wang, Chao,Li, Zhiming,Wang, Quanrui
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p. 2734 - 2746
(2015/10/28)
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- IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives
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Oxidative cyclization of 6-chloro-4-pyrimidinylhydrazones 4 with iodobenzene diacetate (IBD) in dichloromethane gives rise to [1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-o. These incipient products undergo feasible Dimroth rearrangement to furnish the isolated [1,2,4]triazolo[1,5-c]pyrimidines 6a-o in moderate to high yields.
- Tang, Caifei,Li, Zhiming,Wang, Quanrui
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p. 2629 - 2634
(2014/01/06)
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- SUBSTITUTED DIHYDROPYRAZOLONES AND USE THEREOF AS HIF-PROLYL-4 -HYDROXYLASE INHIBITORS
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The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological diseases and kidney diseases, and for promoting wound healing.
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Page/Page column 15
(2012/10/23)
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- A convenient route for the synthesis of novel 2-substituted [1,2,4]triazolo[1,5- C ]pyrimidine derivatives
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Reactions of easily accessible chloropyrimidinyl hydrazones with bromine were investigated. Oxidative cyclization followed by concomitant bromination led to the formation of [1,2,4]triazolo[4,3-c]pyrimidines, which then underwent the Dimroth rearrangement to afford highly functionalized 2-substituted [1,2,4]triazolo[1,5-c]pyrimidines.
- Li, Chao,Li, Zhiming,Wang, Quanrui
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supporting information; experimental part
p. 2179 - 2183
(2010/11/02)
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- SUBSTITUTED DIHYDROPYRAZOLONES FOR TREATING CARDIOVASCULAR AND HEMATOLOGICAL DISEASES
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The invention relates to dihydropyrazolon-derivatives of formula (I), to methods for their production, to their use for treating and/or for preventing diseases and their use for producing medicaments for treating and/or for preventing diseases, in particular cardiovascular and haematological diseases, kidney diseases and for promoting the healing of wounds.
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Page/Page column 16
(2010/12/29)
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- SUBSTITUTED DIHYDROPYRAZOLONES AND THEIR USE
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The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and haematological diseases and kidney diseases, and for promoting wound healing.
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- COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, ARG, BCR-Abl, BRK, EphB, Fms, Fyn, KDR, c-Kit, LCK, PDGF-R, b-Raf, c-Raf, SAPK2, Src, Tie2 and TrkB kinases.
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(2008/06/13)
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