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Stefano Della Longa, Alessandro Arcovito
Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i...
January 16, 2018: Journal of Computer-aided Molecular Design
Haydi Saher ElBordiny, Mostafa Mahmoud El-Miligy, Shaymaa Emam Kassab, Hoda Daabees, Soad Abdelhamid Mohamed El-Hawash, Waleed Ali Mohamed Ali
New candidates of 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives (4-7) were designed combining the pyrazoline/isoxazoline heterocycles and 2-phenylindole to explore its potential as 15-lipoxygenase (15-LOX) inhibitors. The design of the new derivatives was based on utilizing the antioxidant properties of pyrazoline, 2-phenylindole and the good 15-LOX inhibition properties of indolylpyrazoline. The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields...
January 10, 2018: European Journal of Medicinal Chemistry
Mamdouh A Abu-Zaied, Galal H Elgemeie
The easy, convenient and high yielding preparation of new thioglycosides incorporating mercaptopyrazolo[1,5-a]pyrimidine moieties from readily accessible starting materials has been reported. The main step of this protocol is the formation of 7-mercaptopyrazolo[1,5-a]pyrimidine-6-carbonitrile derivatives 4a-d by condensation of sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate) 1 with 4-(aryldiazenyl)-1H-pyrazole-3,5-diamines 3a-d to form target compounds 4a-d, which coupled with tetra-O-acetyl-α-D-glycopyranosyl bromides 5a,b in the presence of basic medium to provide the corresponding product purine thioglycoside analogs 6a-h...
January 16, 2018: Nucleosides, Nucleotides & Nucleic Acids
Wan-Chen Cindy Lee, Wei Wang, Jie Jack Li
2-Aminophenyl-1H-pyrazole has been identified as a viable directing group to promote copper(II)-mediated ortho-selective sp2 C-H bond tandem alkynylation/annulation of anilides with terminal alkynes to offer arylmethylene isoindolinones. Meanwhile, copper(II)-mediated ortho-selective sp2 C-H hydroxylation of anilides has also been optimized as the major reaction pathway by using Cu(OAc)2 as the promoter and 1,1,3,3-tetramethylguanidine as an organic base. Recovery of the directing group was achieved by hydrazinolysis for arylmethylene isoindolinones and basic hydrolysis for the hydroxylation products, respectively...
January 15, 2018: Journal of Organic Chemistry
Sahar Yousuf, Khalid Mohammed Khan, Uzma Salar, Almas Jabeen, Shakil Ahmed, Munira Taj Muhammad, Aisha Faheem, Shahnaz Perveen
BACKGROUND: Pyrazolones have identified as significant antioxidant agents and many marketed and clinically prescribed NSAIDs have pyrazolone ring as main scaffold. METHOD: Keeping in consideration the antioxidant potential of pyrazolone scaffold, new bis-pyrazolones 3-30 were synthesized by a green and enviroment friendly reaction route, in which two equivalents of 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-ol were treated with one equivalent of benzaldehyde derivatives without any catalyst...
January 12, 2018: Medicinal Chemistry
Khalid Karrouchi, Smaail Radi, Youssef Ramli, Jamal Taoufik, Yahia N Mabkhot, Faiz A Al-Aizari, M'hammed Ansar
Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety...
January 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Martin Pisár, Eva Schütznerová, Filip Hančík, Igor Popa, Zdeněk Trávníček, Petr Cankař
The cyclin-dependent kinase inhibitor, CAN508, was protected with di-tert-butyl dicarbonate to access the amino-benzoylated pyrazoles. The bromo derivatives were further arylated by Suzuki-Miyaura coupling using the XPhos Pd G2 pre-catalyst. The coupling reaction provided generally the para-substituted benzoylpyrazoles in the higher yields than the meta-substituted ones. The Boc groups were only utilized as directing functionalities for the benzoylation step and were hydrolyzed under conditions of Suzuki-Miyaura coupling, which allowed for elimination of the additional deprotection step...
January 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Alexey S Berezin, Katerina A Vinogradova, Vladimir A Nadolinny, Taisiya S Sukhikh, Viktor P Krivopalov, Elena B Nikolaenkova, Mark B Bushuev
A mononuclear manganese(ii) complex with a chelating 4-(3,5-diphenyl-1H-pyrazol-1-yl)-6-(piperidin-1-yl)pyrimidine ligand (L), [MnL2Cl2]·H2O, shows intriguing excitation wavelength-dependent emission. Depending on the excitation wavelength, the complex demonstrates three emission bands with the maxima at 380 nm, 440 nm and 495 nm. The 380 nm and 440 nm emissions originate from the π → π* and n → π* ligand-centered transitions. The long-wave 495 nm emission with microsecond lifetimes is related to the d-d transitions and/or metal-to-ligand and halogen-to-ligand charge transfer...
January 12, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Simone Carradori, Daniela Secci, Jacques P Petzer
Monoamine oxidase (MAO) inhibitors, after the initial "golden age", are currently used as third-line antidepressants (selective MAO-A inhibitors) or clinically enrolled as co-adjuvants for neurodegenerative diseases (selective MAO-B inhibitors). However, the research within this field is always increasing due to their pivotal role in modulating synaptic functions and monoamines metabolism. Areas covered: In this paper, MAO inhibitors (2015-2017) are disclosed ordering all the patents according to their chemical scaffold...
January 11, 2018: Expert Opinion on Therapeutic Patents
Adrian Huang, Kellie Wo, So Yeun Christine Lee, Nika Kneitschel, Jennifer Chang, Kathleen Zhu, Tatsiana Mello, Laura Bancroft, Natalie Norman, Shao-Liang Zheng
No abstract text is available yet for this article.
January 10, 2018: Journal of Organic Chemistry
Pulakesh Das, Satoshi Gondo, Etsuko Tokunaga, Yuji Sumii, Norio Shibata
The synthesis of pyrazole triflones containing a triflyl group at the 3-position is disclosed. Treatment of 2-diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one with nitroalkenes under basic conditions gave pharmaceutically attractive pyrazole 3-triflones in good to high yields. The generation of anionic triflyldiazomethane species followed by the [3 + 2] cycloaddition reaction with nitroalkenes is proposed for this transformation. 3-(Difluoromethanesulfonyl)pyrazoles were also synthesized by using a previously unknown anionic (difluoromethanesulfonyl)diazomethane species under a similar strategy...
January 10, 2018: Organic Letters
Branislav Lukić, Uroš Grošelj, Marko Novinec, Jurij Svete
Eight novel 5-(N-Boc-N-benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides were prepared in three steps from methyl 3-amino-1H-pyrazole-4-carboxylate and methyl 5-(benzyl(tert-butoxycarbonyl)amino)-3-oxopentanoate. The synthetic procedure comprises cyclocondensation of the above starting compounds, hydrolysis of the ester, and bis(pentafluorophenyl) carbonate (BPC)-mediated amidation. Title carboxamides were tested for inhibition of cathepsins K and B. The N-butylcarboxamide 5a exhibited appreciable inhibition of cathepsin K (IC50 ~ 25 μM), while the strongest inhibition of cathepsin B was achieved with N-(2-picolyl)carboxamide 5c (IC50 ~ 45 μM)...
December 2017: Acta Chimica Slovenica
Jaka Glavač, Georg Dahmann, Franc Požgan, Sebastijan Ričko, Bogdan Štefane, Jurij Svete, Uroš Grošelj
Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative. The free amines were prepared by acidolytic deprotection. Title compound was also prepared by 'ring switching' transformation of N-Boc-pyrrolin-2(5H)-one with hydrazine hydrate. Hydrogenolytic deprotection of 5-(N-alkyl-N-Cbz-aminomethyl)pyrazolidine-3-ones followed by cyclisation with 1,1'-carbonyldiimidazole (CDI) gave two novel representatives of perhydroimidazo[1,5-b] pyrazole, which is an almost unexplored heterocyclic system...
December 2017: Acta Chimica Slovenica
Hamid Beyzaei, Zahra Motraghi, Reza Aryan, Mohammad Mehdi Zahedi, Alireza Samzadeh-Kermani
Various biological properties of natural and synthetic pyrazole derivatives such as anti-inflammatory, antimicrobial, neuroprotective, anticonvulsant, antidepressant and anticancer activities encouraged us to propose a new, fast, green and eco-friendly procedure for the preparation of some novel 5-amino-3-(aryl substituted)-1-(2,4-dinitrophenyl)-1H-pyrazole-4-carbonitriles. They were efficiently synthesized via one-pot two-step process reaction of malononitrile, 2,4-dinitrophenylhydrazine and different benzaldehydes in deep eutectic solvent (DES) glycerol/potassium carbonate...
December 2017: Acta Chimica Slovenica
Shadia A Galal, Sarah H M Khairat, Hamed I Ali, Samia A Shouman, Yasmin M Attia, Mamdouh M Ali, Abeer E Mahmoud, Abeer H Abdel-Halim, Amal A Fyiad, Ashraf Tabll, Reem El-Shenawy, Yasmine S El Abd, Raghda Ramdan, Hoda I El Diwani
The development of checkpoint kinase 2 (Chk2) inhibitors for the treatment of cancer has been an ongoing and attractive objective in drug discovery. In this study, twenty-one feasible pyrazole-benzimidazole conjugates were synthesized to study their effect against Chk2 activity using Checkpoint Kinase Assay. The antitumor activity of these compounds was investigated using SRB assay. A potentiation effect of the synthesized Chk2 inhibitors was also investigated using the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7)...
December 8, 2017: European Journal of Medicinal Chemistry
Basil Mohammed Ahmed, Gellert Mezei
A simple, inexpensive and highly efficient procedure for the selective deuteration (up to >99% D atom %) of the C-4 position of pyrazole substrates activated by NH2 or OH groups at the C-3(5) position is reported. The deuteration reaction is carried out by simply dissolving the substrate in D2O or other deuterated protic solvents, either in the absence of a catalyst with heating, or under acidic catalysis at ambient temperature; the products are obtained by simple evaporation of the solvent.
January 9, 2018: Journal of Organic Chemistry
Eglė Arbačiauskienė, Sonata Krikštolaitytė, Aiva Mitrulevičienė, Aurimas Bieliauskas, Vytas Martynaitis, Matthias Bechmann, Alexander Roller, Algirdas Šačkus, Wolfgang Holzer
The tautomerism of 1-phenyl-1,2-dihydro-3H-pyrazol-3-One was investigated. An X-ray crystal structure analysis exhibits dimers of 1-phenyl-1H-pyrazol-3-ol units. Comparison of NMR (nuclear magnetic resonance) spectra in liquid state (¹H, 13C, 15N) with those of "fixed" derivatives, as well as with the corresponding solid state NMR spectra reveal this compound to exist predominantly as 1H-pyrazol-3-ol molecule pairs in nonpolar solvents like CDCl₃ or C₆D₆, whereas in DMSO-d₆ the corresponding monomers are at hand...
January 9, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Akiyoshi Kunugi, Yasukazu Tajima, Haruhiko Kuno, Satoshi Sogabe, Haruhide Kimura
Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (AMPA-R) potentiators with brain-derived neurotrophic factor (BDNF)-induction potential could be promising as therapeutic drugs for neuropsychiatric and neurological disorders. However, AMPA-R potentiators such as LY451646 have risks of narrow bell-shaped responses in pharmacological effects, including in vivo BDNF induction. Interestingly, LY451646 and LY451395, other AMPA-R potentiators, showed agonistic effects and exhibited bell-shaped responses in the BDNF production in primary neurons...
January 3, 2018: Journal of Pharmacology and Experimental Therapeutics
Silvia Saueressig, Josiane Tessmann, Rosiane Mastelari, Liziane Pereira da Silva, Julieti Buss, Natalia Vieira Segatto, Karine Rech Begnini, Bruna Pacheco, Cláudio Martin Pereira de Pereira, Tiago Collares, Fabiana Kömmling Seixas
BACKGROUND: Breast cancer is a global public health problem. For some subtypes, such as Claudin-low, the prognosis is poorer and the treatment is still a challenge. Pyrazoles are an important class of heterocyclic compounds and are promising anticancer agents based on their chemical properties. The present study was aimed not only at testing pyrazoles previously prepared by our research group in two breast cancer cell lines characterized by intermediated response to conventional chemotherapy but also at analyzing the possible synergistic effect of these pyrazoles associated with doxorubicin...
December 22, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Maryam A Z El-Attar, Rasha Y Elbayaa, Omaima G Shaaban, Nargues S Habib, Abeer E Abdel Wahab, Ibrahim A Abdelwahab, Soad A M El-Hawash
Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities...
December 5, 2017: Bioorganic Chemistry
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