- Microwave-assisted efficient synthesis of pyrazole-fibrate derivatives as stimulators of glucose uptake in skeletal muscle cells
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The design and synthesis of a series of pyrazolo[3,4-d]pyrimidinones containing fibrate side chains have been accomplished by utilizing the concept of molecular hybridization. All the synthesized compounds were evaluated for the glucose uptake stimulatory effect in L6 rat skeletal muscle cells. Four compounds (3f, 3g, 3j and 3q) were found to show significant stimulation of glucose uptake. Further these four compounds have been examined for their Glut4 translocation stimulatory effect in L6-Glut4myc myotubes. Compound 3q was found to exert maximum increase in GLUT4myc translocation.
- Gupta, Sampa,Kant, Ruchir,Pandey, Shubham,Rai, Amit Kumar,Sashidhara, Koneni V.,Singh, L. Ravithej,Tamrakar, Akhilesh K.
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- COMBINATION THERAPY FOR TREATING MPS1
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The application is directed to compounds of formula (I) and their salts and solvates, wherein B, R1, R2, R3, R3', R4, R4', and R5 are as set forth in the specification, as well as to methods for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., MPS1, optionally in combination with α-L-iduronidase or an analog or variant thereof, e.g., laronidase.
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Paragraph 0311-0314; 0416-0419
(2021/08/14)
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- Synthesis of pyrazole-carboxamides and pyrazole-carboxylic acids derivatives: Simple methods to access powerful building blocks
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Hybrid systems containing pyrazole moiety show a wide spectrum of biological activities. To access novel hybrids with pyrazole ring, in this work we synthesized twenty pyrazole-carboxylic acids and twenty pyrazole-carboxamides, using simple synthetic methods, to be used as building blocks in the development of new structures.
- Dos Santos, Maurício Silva,Ferreira, Byanca Silva,Silva, Rafaela Corrêa,Souto, Bernardo Araújo
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p. 335 - 343
(2021/09/07)
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- Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3
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Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer’s disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1–3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood–brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD.
- Sciú, M. Lourdes,Sebastián-Pérez, Victor,Martinez-Gonzalez, Loreto,Benitez, Rocio,Perez, Daniel I.,Pérez, Concepción,Campillo, Nuria E.,Martinez, Ana,Moyano, E. Laura
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- A Convenient Synthesis of Pyrazole-imidazoline Derivatives by Microwave Irradiation
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A series of 28 hybrids pyrazole-imidazolines 1a–n and 2a–n were synthesized by a new methodology using microwave irradiation, in short time (20–30?min), in low power (50–70?W), and in 34–92% yield. Among all methodologies evaluated, no side products were obtained. All derivatives were completely characterized by FT–IR, 1H and 13C NMR, GC–MS, and HRMS.
- de S. Rosa, Getúlio,Souto, Bernardo A.,Pereira, Cynthia N.,Teixeira, Bruna C.,dos Santos, Maurício S.
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p. 1825 - 1830
(2019/04/30)
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- Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease
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Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease.
- Monteiro,Lechuga,Lara,Souto,Viganó,Bourguignon,Calvet,Oliveira,Alves,Souza-Silva,Santos,Pereira
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- Thermal Ring-Opening of Pyrazolo[3,4-d][1,2,3]triazin-4-ones: An Experimental and Theoretical Study
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Several 3-pyrazolylcarbonyl-pyrazolo[3,4-d][1,2,3]triazin-4-ones have been prepared from 5-amino-1H-pyrazole-4-carbonitriles through a simple sequence. In the first step, diazotization of the corresponding aminopyrazoles afforded pyrazolo[3,4-d][1,2,3]triazin-4-ones. Next, thermal rearrangement of these compounds through nitrogen elimination gave the final products. The proposed mechanism for the ring-opening of the pyrazolotriazinones to give the pyrazolylcarbonyl-pyrazolotriazinones involves the generation of an iminoketene intermediate, which reacts with a second molecule of pyrazolotriazinone. The complete mechanism of product formation involving the iminoketene intermediate, and all other reasonable pathways, have been explored in detail through DFT calculations. Furthermore, additional experiments to corroborate the presence of the iminoketene intermediate were carried out.
- Colomer, Juan P.,Sciú, María L.,Ramirez, Cristina L.,Soria-Castro, Silvia M.,Vera, D. Mariano A.,Moyano, Elizabeth L.
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p. 1514 - 1524
(2018/03/30)
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- Synthesis and biological evaluation of new tacrine analogues under microwave irradiation
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Efficient routes to various kinds of heterocycles incorporating the p-halophenyl moiety have been synthesized. Different pyrrole derivatives have been synthesized, as well, by Thorpe–Ziegler cyclization. Therefore, we synthesized different analogues of tacrine by Friedl?nder reaction of o-amino nitriles (pyrazolo, furano and pyrrolo) with different cycloalkanones. The use of microwave irradiation leads to shorter production times and high product conversion. These synthesized compounds were biologically evaluated by Ellman’s test on acetylcholinesterase inhibition.
- Alshareef, Hossa Fahad,Mohamed, Heba Abd El Hady,Salaheldin, Abdellatif Mohamed
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p. 732 - 738
(2017/08/09)
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- Synthesis, in vitro and in vivo anticancer activity of novel 1-(4-imino-1-substituted-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)urea derivatives
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A series of pyrazolo[3,4-d]pyrimidine and urea hybrids have been designed, synthesized and evaluated for their anticancer activity in vitro and in vivo cancer models. Among them, compounds 28, 30, 33, 36 and 37 showed promising cytotoxicity against tested cancer cell lines. Compound 37 (CBS-1) appeared as the most active derivative and it exhibited better cytotoxicity against all tested cell lines as compared to doxorubicin. CBS-1 successfully inhibited cell cycle progression and displayed good apoptosis in A549 cells. CBS-1 significantly induced caspase-3 activation and suppressed NF-κB and IL-6 activation in immunocytochemistry, qPCR and western blot analysis. Additionally, CBS-1 prominently displayed tumoricidal effects in lung adenocarcinoma in vivo xenograft nude mice model.
- Mishra, Chandra Bhushan,Mongre, Raj Kumar,Kumari, Shikha,Jeong, Dong Kee,Tiwari, Manisha
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p. 24491 - 24500
(2016/03/15)
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- Identification of novel GLUT inhibitors
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The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.
- Siebeneicher, Holger,Bauser, Marcus,Buchmann, Bernd,Heisler, Iring,Müller, Thomas,Neuhaus, Roland,Rehwinkel, Hartmut,Telser, Joachim,Zorn, Ludwig
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p. 1732 - 1737
(2016/07/27)
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- An efficient synthesis of new 5-(1-Aryl-1H-pyrazole-4-yl)-1H-tetrazoles from 1-Aryl-1H-pyrazole-4-carbonitriles via [3 + 2] cycloaddition reaction
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A series of new 5-(1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 4a-l were synthesized via [3 + 2] cycloaddition reaction from 1-aryl-1H-pyrazole-4- carbonitriles 3a-l, sodium azide and ammonium chloride, using dimethylformamide (DMF) as solvent, in good yields: 64-85%. The structures of these newly synthesized compounds were determined from the IR, 1H- and 13C-NMR spectroscopic data and elemental analyses.
- Dos Santos, Mauricio S.,Bernardino, Alice M. R.,Pinheiro, Luiz C. S.,Canto-Cavalheiro, Marilene M.,Leon, Leonor L.
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p. 1425 - 1428
(2013/02/23)
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- Synthesis and antileishmanial activity of new 1-aryl-1H-pyrazole-4- carboximidamides derivatives
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Chemotherapy for leishmaniasis, diseases caused by protozoa of the genus Leishmania, remains inefficient in several treatments. So there is a need to search for new drugs. In this work, we have synthesized 1-aryl-1H-pyrazole-4- carboximidamides derivatives and evaluated antileishmanial activities in vitro, as well as cytotoxic effects. Structure-activity relationship (SAR) studies were carried out with all the compounds of the series. Compound 2 showed an activity profile that can be improved through medicinal chemistry strategies.
- Dos Santos, Mauri?cio S.,Gomes, Adriana O.,Bernardino, Alice M. R.,De Souza, Marcos C.,Khan, Misbahul A.,De Brito, Monique A.,Castro, Helena C.,Abreu, Paula A.,Rodrigues, Carlos R.,De Le?o, Rosa M. M.,Leon, Leonor L.,Canto-Cavalheirr, Marilene M.
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experimental part
p. 352 - 358
(2011/10/04)
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- New application of heterocyclic diazonium salts. Synthesis of pyrazolo[3,4-d][1,2,3]triazin-4-ones and imidazo[4,5-d][1,2,3]triazin-4-ones
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The pyrazolo[3,4-d][1,2,3]triazin-4-ones 3 and imidazo[4,5-d][1,2,3] triazin-4-ones 4 are analogs structurally related to purines that have showed a wide and significant variety of biological activity. These compounds were synthesized by one-pot diazotization of 5-amino-1H-pyrazole-4-carbonitriles 1 and 5-amino-1H-imidazole-4-carbonitriles 2, respectively.
- Colomer, Juan Pablo,Moyano, Elizabeth Laura
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supporting information; scheme or table
p. 1561 - 1565
(2011/05/05)
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- Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines
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General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.
- Daniels, R. Nathan,Kim, Kwangho,Lebois, Evan P.,Muchalski, Hubert,Hughes, Mary,Lindsley, Craig W.
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p. 305 - 310
(2008/09/17)
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- Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors
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Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC50 values below 1 μM. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors.
- Gupta, Sanjay,Rodrigues, Ligia M.,Esteves, Ana P.,Oliveira-Campos, Ana M.F.,Nascimento, M. Sao Jose,Nazareth,Cidade, Honorina,Neves, Marta P.,Fernandes, Eduarda,Pinto, Madalena,Cerqueira, Nuno M.F.S.A.,Bras, Natercia
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p. 771 - 780
(2008/09/20)
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- 3-AMINO-PYRAZOLE-4-CARBOXAMIDE DERIVATIVES USEFUL AS INHIBITORS OF PROTEIN KINASES
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The invention relates to novel heterocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them
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Page/Page column 41
(2008/12/05)
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- Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines
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A new approach to the synthesis of 5-amino-4-cyanopyrazoles has been developed, utilising a novel flow microwave device. These products are then converted by a batch mode microwave process to structurally more complex dimeric and 'mixed' pyrazolopyrimidine structures. The Royal Society of Chemistry.
- Smith, Catherine J.,Iglesias-Sigueenza, Francisco Javier,Baxendale, Ian R.,Ley, Steven V.
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p. 2758 - 2761
(2008/03/11)
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- PYRAZOLOPYRIMIDINES AS KINASE INHIBITORS
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The present invention relates generally to inhibitors of the kinases and more particularly to novel pyrazolopyrimidine compounds.
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- Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors
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A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar1) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range.
- Peat, Andrew J.,Boucheron, Joyce A.,Dickerson, Scott H.,Garrido, Dulce,Mills, Wendy,Peckham, Jennifer,Preugschat, Frank,Smalley, Terrence,Schweiker, Stephanie L.,Wilson, Jayme R.,Wang, Tony Y.,Zhou, Huiqiang Q.,Thomson, Stephen A.
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p. 2121 - 2125
(2007/10/03)
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