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https://www.readbyqxmd.com/read/28545167/synthesis-of-s-2-s-3-4-chlorophenyl-n-4-chlorophenyl-sulfonyl-4-phenyl-4-5-dihydro-1h-pyrazole-1-carboximidamido-3-methyl-d3-butanamide-d5-octa-deuterated-jd5037
#1
Malliga R Iyer, Resat Cinar, Nathan J Coffey, Robert J Chorvat, George Kunos
JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB1 R) receptor. Peripheral CB1 receptor antagonists/inverse agonists have great potential in the treatment of metabolic disorders like type 2 diabetes, obesity and NASH. We report the synthesis of octa-deuterated [(2) H8 ]-JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L-valine-d8 starting material. The [(2) H8 ]-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard...
May 25, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28544160/a-unified-continuous-flow-assembly-line-synthesis-of-highly-substituted-pyrazoles-and-pyrazolines
#2
Joshua Britton, Timothy F Jamison
A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst free conditions...
May 25, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28543913/from-ligand-to-phosphor-rapid-machine-assisted-syntheses-of-substituted-iridium-iii-pyrazolate-complexes-with-tuneable-luminescence
#3
Simon J Pope, Lara Groves, Christiane Schotten, Joseph Beames, James Platts, Duncan Browne, Simon Coles, Peter Horton
A first generation machine-assisted approach towards the preparation of hybrid ligand/metal materials has been explored. A comparison of synthetic approaches demonstrates that incorporation of both flow chemistry and microwave heating, can be successfully applied to the rapid synthesis of a range of new phenyl-1H-pyrazoles (ppz) substituted with electron withdrawing groups (-F, -CF3, -OCF3, -SF5), and these, in turn, can be translated in to heteroleptic complexes, [Ir(ppz)2(bipy)]BF4 (bipy = 2,2'-bipyridine)...
May 22, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28541707/identification-of-a-potent-selective-and-efficacious-phosphatidylinositol-3-kinase-%C3%AE-pi3k%C3%AE-inhibitor-for-the-treatment-of-immunological-disorders
#4
Qingjie Liu, Qing Shi, David Marcoux, Douglas G Batt, Lyndon Cornelius, Lan-Ying Qin, Zheming Ruan, James Neels, Myra Beaudoin Bertrand, Anurag S Srivastava, Ling Li, Robert Joseph Cherney, Hua Gong, Scott H Watterson, Carolyn Weigelt, Kathleen M Gillooly, Kim W McIntyre, Jenny H Xie, Mary T Obermeier, Aberra Fura, Bogdan Sleczka, Kevin Stefanski, R Marcus Fancher, Shweta Padmanabhan, Thatipamula Rp, Ipsit Kundu, Kallem Rajareddy, Rodney Smith, James K Hennan, Dezhi Xing, Jingsong Fan, Paul C Levesque, Qian Ruan, Sidney Pitt, Rosemary Zhang, Donna Pedicord, Jie Pan, Melissa Yarde, Hao Lu, Jonathan Lippy, Christine Goldstine, Stacey Skala, Richard A Rampulla, Arvind Mathur, Anuradha Gupta, Pirama Nayagam Arunachalam, John S Sack, Jodi K Muckelbauer, Mary Ellen Cvijic, Luisa M Salter-Cid, Rajeev S Bhide, Michael A Poss, John Hynes, Percy H Carter, John E Macor, Stefan Ruepp, Gary L Schieven, Joseph A Tino
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work towards the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28541696/reversible-redox-activity-in-multicomponent-metal-organic-frameworks-constructed-from-trinuclear-copper-pyrazolate-building-blocks
#5
Binbin Tu, Qingqing Pang, Huoshu Xu, Xiaomin Li, Yulin Wang, Zhen Ma, Linhong Weng, Qiaowei Li
Inorganic functionalization of metal-organic frameworks (MOFs), such as incorporating multiple inorganic building blocks with distinct metals into one structure and further modulating the metal charges, endows the porous materials with significant properties towards their applications in catalysis. In this report, by exploring the role of 4-pyrazolecarboxylic acid (H2PyC) in the formation of trinuclear copper pyrazolate as a metalloligand in situ, four new MOFs with multiple components in order were constructed through one-pot synthesis...
May 25, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28525816/evaluation-of-the-toxicity-of-herbicide-topramezone-to-chlorella-vulgaris-oxidative-stress-cell-morphology-and-photosynthetic-activity
#6
Fangfang Zhao, Qingqing Xiang, Ying Zhou, Xiao Xu, Xinyi Qiu, Yi Yu, Farooq Ahmad
Topramezone is a new, highly selective herbicide of pyrazole structure for the post-emergence control of broadleaf and grass weeds in corn. In this study, the effects of topramezone on C. vulgaris, especially in relation to the cell growth, oxidative stress, cell morphology and photosynthetic activity were assessed. Results showed that topramezone treatment was detrimental to C. vulgaris growth during the 24-96h of exposure. The changes in cells pigments content and relative transcript of photosynthesis-related genes, which implies that topramezone disrupted the photosynthetic system...
May 16, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28518069/modification-and-functionalization-of-the-guanidine-group-by-tailor-made-precursors
#7
Tobias G Kapp, Maximilian Fottner, Horst Kessler
The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes αv and α5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document...
April 27, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28512031/from-a-novel-hts-hit-to-potent-selective-and-orally-bioavailable-kdm5-inhibitors
#8
Jun Liang, Sharada Labadie, Birong Zhang, Daniel F Ortwine, Snahel Patel, Maia Vinogradova, James R Kiefer, Till Mauer, Victor S Gehling, Jean-Christophe Harmange, Richard Cummings, Tommy Lai, Jiangpeng Liao, Xiaoping Zheng, Yichin Liu, Amy Gustafson, Erica Van der Porten, Weifeng Mao, Bianca M Liederer, Gauri Deshmukh, Le An, Yingqing Ran, Marie Classon, Patrick Trojer, Peter S Dragovich, Lesley Murray
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512022/synthesis-antimycobacterial-activity-and-docking-study-of-2-aroyl-1-benzopyrano-4-3-c-pyrazol-4-1h-one-derivatives-and-related-hydrazide-hydrazones
#9
Violina T Angelova, Violeta Valcheva, Tania Pencheva, Yulian Voynikov, Nikolay Vassilev, Rositsa Mihaylova, Georgi Momekov, Boris Shivachev
A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-g and coumarin containing hydrazide-hydrazone analogues 4a-e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28-1.69μM, which were comparable to those of isoniazid. The cytotoxicity (IC50>200µM) to the "normal cell" model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-e, was noticeably milder compared to that of their hydrazone analogues 4a-e (IC50 33-403µM)...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28509884/one-flask-synthesis-of-pyrazolo-3-4-d-pyrimidines-from-5-aminopyrazoles-and-mechanistic-study
#10
Wan-Ping Yen, Shuo-En Tsai, Naoto Uramaru, Hiroyuki Takayama, Fung Fuh Wong
A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr₃. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions thus involved Vilsmeier amidination, imination reactions, and the sequential intermolecular heterocyclization. To study the reaction mechanism, a series of 4-formyl-1,3-diphenyl-1H-pyrazol-5-yl-N,N-disubstituted formamidines, which were conceived as the chemical equivalent of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl-formamidine, were prepared and successfully converted into pyrazolo[3,4-d]pyrimidines...
May 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28507705/acid-and-au-i-mediated-synthesis-of-hexathymidine-dna-heterocycle-chimeras-an-efficient-entry-to-dna-encoded-libraries-inspired-by-drug-structures
#11
Mateja Klika Škopić, Hazem Salamon, Olivia Bugain, Kathrin Jung, Anne Gohla, Lara J Doetsch, Denise Dos Santos, Avinash Bhat, Bernd Wagner, Andreas Brunschweiger
Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28504843/a-novel-synthetic-chemical-entity-upei-800-is-neuroprotective-in-vitro-and-in-an-in-vivo-rat-model-of-oxidative-stress
#12
Tarek M Saleh, Monique C Saleh, Barry J Connell, Inan Kucukkaya, Alaa S Abd-El-Aziz
In this study, we tested a novel synthetic pyrazole-containing compound, 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (APPC), as an antioxidant in both in vitro and in vivo models of oxidative stress. In addition, the utility of covalently combining APPC with another well-established antioxidant, lipoic acid (LA), was also tested in both models. The in vitro results demonstrated that pretreatment with APPC in a mixed neuronal-glial culture exposed to oxygen-glucose deprivation (OGD) followed by reoxygenation-refeeding, resulted in significant neuroprotection at concentrations between 2...
May 15, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28503856/pyrazole-4-3-h-quinoline-ligand-based-iridium-iii-complexes-for-electrochemiluminescence
#13
Luisa De Cola, Chien-Wei Hsu, Elena Longhi, Stephan Sinn, Chris Hawes Hawes, David Young, Paul Kruger
Electrochemiluminescence (ECL) based on [Ru(bpy)3]2+ systems is widely utilized for immunoassays. In order to extend the promising potential of ECL based applications, Ir(III) complexes have recently attracted attention as probes because of their excellent luminescent properties and tunable emission wavelength. Here we describe a series of Ir complexes using a large π-conjugated ligand and different ancillary chelates. The complexes synthesized have been chemically and spectroscopically characterized and used for ECL measurements with annihilation and co-reactant methods...
May 14, 2017: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/28501903/coumarin-pyrazole-hybrid-with-red-shifted-esipt-emission-and-aie-characteristics-a-comprehensive-study
#14
Milind R Shreykar, Nagaiyan Sekar
The newly synthesized three coumarin pyrazole hybrid excited state intramolecular proton transfer (ESIPT) dyes show efficient charge transfer from the pyrazole ring and the coumarin towards the electron withdrawing dicyanovinylene group as revealed from the frontier molecular orbitals. Aggregation induced emission enhancement (AIEE) studies with 2-((3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene) malononitrile showed 9 fold increase in the emission enhancement in 90% DMF-H2O mixture...
May 13, 2017: Journal of Fluorescence
https://www.readbyqxmd.com/read/28499169/two-novel-dinuclear-ellipsoid-ni-ii-and-co-ii-complexes-bridged-by-4-5-bis-pyrazol-1-yl-phthalic-acid-synthesis-structural-characterization-and-biological-evaluation
#15
Enjun Gao, Zhenzhen Qi, Yun Qu, Yuqing Ding, Yang Zhan, Na Sun, Shaozhong Zhang, Xue Qiu, Mingchang Zhu
Two novel complexes, [Ni2(L)2(H2O)3]·4(H2O) (1) and [Co2(L)2(H2O)3]·5(H2O) (2) [H2L = 4,5-bis(pyrazol-1-yl) phthalic acid] were synthesized and characterized by spectroscopy (IR, (1)H NMR), and elemental analysis. The structures for the complexes were determined by X-ray crystallography providing the dinuclear ellipsoid Ni(II) and Co(II) complexes bridged by 4,5-bis(pyrazol-1-yl)phthalic acid ligands with same coordination modes. The interaction capacity of the complexes with FS-DNA (fish sperm DNA) has been investigated by UV and fluorescence spectroscopy...
May 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28497408/novel-turn-on-fluorescence-probes-for-al-3-based-on-conjugated-pyrazole-schiff-base
#16
Fanwei Wang, Hongdong Duan, Dianxiang Xing, Geng Yang
One novel turn-on fluorescence probe founded on conjugated pyrazole Schiff base for detecting Al(3+) was invented. The UV-vis and fluorescence spectrometer were employed to explore optical properties of this probe. The results got from those experiments indicated that this fluorescence probe manifested excellent sensitivity and selectivity for Al(3+) compared with other cations examined(Ag(+), Co(2+), Mg(2+), Cu(2+), Ni(2+), Pb(2+),and Zn(2+)). In addition, this probe displayed a more rapid response and remained stable between pH 6 and 9 by investigating the fluorescence intensity under different response time and various pH values...
May 11, 2017: Journal of Fluorescence
https://www.readbyqxmd.com/read/28489088/cfa-4-a-fluorinated-metal-organic-framework-with-exchangeable-interchannel-cations
#17
J Fritzsche, M Grzywa, D Denysenko, V Bon, I Senkovska, S Kaskel, D Volkmer
The syntheses and crystal structures of the fluorinated linker 1,4-bis(3,5-bis(trifluoromethyl)-1H-pyrazole-4-yl)benzene (H2-tfpb; 1) and the novel metal-organic framework family M[CFA-4] (Coordination Framework Augsburg University-4), M[Cu5(tfpb)3] (M = Cu(i), K, Cs, Ca(0.5)), are described. The ligand 1 is fully characterized by single crystal X-ray diffraction, photoluminescence-, NMR-, IR spectroscopy, and mass spectrometry. The copper(i)-containing MOF crystallizes in the hexagonal crystal system within the chiral space group P6322 (no...
May 10, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28488743/photoisomerisation-of-bis-tridentate-2-6-bis-1h-pyrazol-1-yl-pyridine-ligands-exhibiting-a-multi-anthracene-skeleton
#18
Ivan Salitros, Olaf Fuhr, Miroslav Gal, Michal Valasek, Mario Ruben
A novel molecular design is described where two peripheral moieties made of 2,6-bis(1H-pyrazol-1-yl)pyridine are linked via a multi-1,8-diethynylanthracene moieties. The optimized synthesis of the three isostructural analogues 1a, 1b and 1c, containing the respective anthraquinone, anthracene and 10-methoxyanthracene units, is reported. The resulting spatial face-to-face arrangement of the peripheral anthracene rings enables to trigger the intramolecular [4+4] photocycloadition affording P1b and P1c isomers, which can be thermally cleaved back to the original anthracene derivatives 1b and 1c...
May 10, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28487127/design-and-synthesis-of-pyrazolo-3-4-d-pyrimidines-nitric-oxide-releasing-compounds-targeting-hepatocellular-carcinoma
#19
Yaseen A M M Elshaier, Mohamed A Shaaban, Mohammed K Abd El Hamid, Mostafa H Abdelrahman, Mahrous A Abou-Salim, Sara M Elgazwi, Fathi Halaweish
A new series of pyrazolo[3,4-d]pyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) protein assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC50=3, 5, 3 and 5μM, respectively, compared to erlotinib as a reference drug (IC50=25μM)...
March 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28487075/n-1h-pyrazol-3-yl-quinazolin-4-amines-as-a-novel-class-of-casein-kinase-1%C3%AE-%C3%AE%C2%B5-inhibitors-synthesis-biological-evaluation-and-molecular-modeling-studies
#20
Chandrabose Karthikeyan, Pramod Jharia, Digambar Kumar Waiker, Amy Catherine Nusbaum, Haneen Amawi, Erin Marie Kirwen, Ryann Christman, Sri Krishna Chaitanya Arudra, Laurent Meijer, Amit K Tiwari, Piyush Trivedi
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line...
April 27, 2017: Bioorganic & Medicinal Chemistry Letters
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