- Pyridazine N-Oxides as Photoactivatable Surrogates for Reactive Oxygen Species
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A method for the photoinduced evolution of atomic oxygen from pyridazine N-oxides was developed. This underexplored oxygen allotrope mediates arene C-H oxidation within complex, polyfunctional molecules. A water-soluble pyridazine N-oxide was also developed and shown to promote photoinduced DNA cleavage in aqueous solution. Taken together, these studies highlight the utility of pyridazine N-oxides as photoactivatable O(3P) precursors for applications in organic synthesis and chemical biology.
- Basistyi, Vitalii S.,Frederich, James H.
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supporting information
p. 1907 - 1912
(2022/03/27)
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- Structure-based discovery of receptor tyrosine kinase AXL degraders with excellent anti-tumor activity by selectively degrading AXL and inducing methuosis
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The receptor tyrosine kinase (RTK) anexelekto (AXL) is mutated and/or overexpressed in various malignancies, and plays a central role in tumor development and acquired drug resistance. Although highly selective inhibitors have been developed in recent years, direct inhibition of AXL may block its ubiquitination, eventually leading to surface accumulation of the protein. Herein, we designed and synthesized a series of AXL degraders with high selectivity and without compensatory increase of AXL. In particular, compounds 20 and 22 showed significant AXL degradation capacity, which inhibited the proliferation and migration of cancer cells in vitro. In addition, these compounds induced the formation of cytoplasmic vacuoles and triggered methuosis, a new type of non-apoptotic cell death, by stimulating excessive production of macropinosomes. Vacuole formation was mediated via H-Ras activation, and was attenuated upon inhibition of its downstream regulatory factor Rac1. Furthermore, compound 20 inhibited the growth of tumor cell xenografts in vivo, and prolonged the survival of the tumor-bearing mice.
- Chen, Shuang,Chi, Fanglian,Feng, Ziying,Huang, Wenlong,Jia, Huiting,Jiang, Yuxuan,Qian, Hai,Qiu, Qianqian,Shi, Wei,Zhong, Yue,Zhou, Jiaqi
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- Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies
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Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor receptor (EGFR) inhibition showed that compounds IXn, IXg, IXb and IXl exhibited excellent inhibitory effect (IC50 = 0.65, 0.75, 0.82 and 0.84 μM, respectively) compared to Erlotinib (IC50 = 0.95 μM). The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compounds IXg and IXn due to their significant EGFR inhibition. Flow cytometeric analysis indicated that compounds IXg and IXn result in increased cell numbers in phase G2/M, suggesting cell cycle arrest in phase G2/M in UO-31cells. Furthermore, real time PCR assay illustrated that compounds IXg and IXn elevated Bax/Bcl2 ratio which confirmed the mechanistic pathway of them. Moreover, the apoptotic induction of UO-31 renal cancer cells was enhanced effectively through activation of caspase-3 by compounds IXg and IXn. On the other hand, molecular docking study was performed to investigate binding mode of interaction of compounds with EGFR-PK in the active site with the aim of rationalizing its promising inhibitory activity. Finally, based on the aforementioned findings, compounds IXg and IXn could be considered as effective apoptosis modulators and promising leads for future development of new anti-renal cancer agents.
- Ahmed, Marwa F.,Santali, Eman Y.,Mohi El-Deen, Eman M.,Naguib, Ibrahim A.,El-Haggar, Radwan
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- Lewis Acid Directed Regioselective Metalations of Pyridazine
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Mono- or bidentate boron Lewis acids trigger a regioselective magnesiation or zincation of pyridazine in position C3 (ortho product) or C4 (meta product). The regioselectivity of the metalation was rationalized with the help of calculated pKa values of both pyridazine and pyridazine/Lewis acid complexes.
- Balkenhohl, Moritz,Jangra, Harish,Lenz, Tobias,Ebeling, Marian,Zipse, Hendrik,Karaghiosoff, Konstantin,Knochel, Paul
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supporting information
p. 9244 - 9247
(2019/06/04)
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- Novel Triazolo Pyridazine Derivatives and Use Thereof
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The present invention relates to a novel triazolo pyridazine derivative or a pharmaceutically acceptable salt thereof, to a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity and a pharmaceutical composition for preventing or treating an abnormal proliferation disorder (hyperproliferative disorder) comprising same as an active ingredient, and to a method for preventing or treating an abnormal proliferation disorder (hyperproliferative disorder) comprising a step of administering a pharmaceutically effective amount of the pharmaceutical composition to a subject in need thereof. The present invention can advantageously be used as a therapeutic agent for various abnormal proliferation disorders such as cancer, psoriasis, rheumatoid arthritis and diabetic retinopathy which are associated with excessive cell proliferation and growth due to irregular kinase activity by effectively suppressing the activity of c-Met tyrosine kinase.
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Paragraph 0216; 0218-0220
(2018/07/31)
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- Synthesis, vasorelaxant activity and 2D-QSAR study of some novel pyridazine derivatives
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Novel 3,6-disubstituted pyridazines were synthesized by facile method and screened for their vasorelaxant properties utilizing isolated thoracic rat aortic rings. Compounds 8a and 11a exerted potent vasorelaxant activity (IC50 = 198 and 177 μM, respectively) relative to doxazosin mesylate (used reference standard, IC50 = 226 μM), that, they may represent promising hits for treatment of cardiovascular disorders. The observed activity was validated by a statistically significant QSAR model (N = 32, n = 6, R2 = 0.811782, R2cvOO = 0.7153, R2cvMO = 0.7209, F = 17.9708, s2 = 9.65226 × 10-8) that was obtained employing CODESSA-Pro software.
- George, Riham F.,Saleh, Dalia O.
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p. 663 - 673
(2016/01/09)
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- Synthesis and cytotoxic activities of some pyrazoline derivatives bearing phenyl pyridazine core as new apoptosis inducers
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The cyclization of chalcones 3a-3u with 3-hydrazinyl-6-phenylpyridazine 7 under basic condition led to the formation of new pyrazoline derivatives 8a-8u. All final compounds were characterized by spectral and elemental analyses. They were screened for their antiproliferative activities against A549 (lung), HepG-2 (liver), CaCo-2 (intestinal) and MCF-7 (breast) cancer cell lines. Some of the synthesized compounds exhibited promising antiproliferative activities especially compound 8k with IC50values of 8.33, 1.67 and 10?μM against HepG-2, MCF-7 and CaCo-2 cancer cell lines, respectively. Moreover, their antiproliferative activity was due to apoptosis rather than necrosis induction except compound 8h which exhibited equal apoptotic and necrotic properties. Compound 8k showed 5 fold increase in caspase-3 activity indicating that the apoptosis proceeds via caspase-3 activation.
- George, Riham F.,Fouad, Marwa A.,Gomaa, Iman E.O.
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- Pd-catalyzed chemoselective cross-coupling reaction of triaryl- or triheteroarylbismuth compounds with 3,6-dihalopyridazines
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The cross-coupling reactions of 3,6-dihalopyridazines with triaryl- or triheteroarylbismuth compounds were performed under palladium catalysis. The reaction was highly chemoselective, affording functionalized aryl- or heteroarylpyridazinyl chlorides in moderate to good yields. The cross-coupling reactions of 3,6-dihalopyridazines with triaryl- or triheteroarylbismuth compounds were performed under palladium catalysis. The reaction was highly chemoselective, affording functionalized aryl- or heteroarylpyridazinyl chlorides in moderate to good yields. Copyright
- Urgin, Karene,Aube, Christophe,Pipelier, Muriel,Blot, Virginie,Thobie-Gautier, Christine,Sengmany, Stephane,Lebreton, Jacques,Leonel, Eric,Dubreuil, Didier,Condon, Sylvie
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supporting information
p. 117 - 124
(2013/02/22)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT OF ARTHRITIS
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The invention relates to compounds, compositions, formulations and dosage forms comprising N-(Cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3- amine, or a pharmaceutically acceptable salt thereof, and methods for treating arthritis in a subject using such compounds, compositions, formulations and dosage forms.
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Page/Page column 38
(2012/02/13)
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- Design, synthesis and analgesic properties of novel conformationally-restricted N-acylhydrazones (NAH)
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A set of six azaheterocycles were designed as conformationnaly-constrained N-acylhydrazones and tested as analgesics.
- Kuemmerle, Arthur E.,Vieira, Marina M.,Schmitt, Martine,Miranda, Ana L.P.,Fraga, Carlos A.M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
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scheme or table
p. 4963 - 4966
(2010/03/24)
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- Synthesis, antitubercular, antifungal and antibacterial activities of 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3, 4,5-tetrahydropyridazin-3-one
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A series of 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3,4,5-tetrahydropyridazin-3-ones has been synthesized. An appropriate aromatic hydrocarbon reacts with succinic anhydride in presence of AlCl3 to yield β-aroyl propionic acid. The corresponding acid was cyclized with hydrazine hydrate to give 6-(substituted aryl)-2,3,4,5- tetrahydro-3-pyridazinone, which was heated on steam bath with phosphorus( V) oxychloride to yield 3-chloro 6-substituted phenyl pyridazine. This intermediate after reaction with hydrazine hydrate was converted into 3-hydrazino-6- substituted phenyl pyridazine. The resulting product was converted into 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3, 4,5-tetrahydropyridazin-3-one by reacting with substituted aroyl propionic acid. Spectral data (IR, NMR, mass spectra) confirmed the structures of the synthesized compounds. The synthesized compounds were investigated for their in vitro antitubercular, antifungal and antibacterial activities. The results indicated that the synthesized compounds have mild to potent activities with reference to their appropriate reference standards.
- Islam, Mojahidul,Siddiqui, Anees A.,Rajesh, Ramadoss
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experimental part
p. 353 - 362
(2009/04/11)
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- Isonitriles as efficient ligands in Suzuki-Miyaura reaction
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Isonitrile palladium complexes [(RNC)2PdCl2] were prepared and tested in Suzuki reaction of 4-chloroanisol. (AdNC)2PdCl2 was found the most effective catalyst and was used in phenylation of several chloro and bromoaromatic substrates.
- Villemin, Didier,Jullien, Arnaud,Bar, Nathalie
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p. 4191 - 4193
(2008/02/05)
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- Mono- or diphenylpyridazines connected to N-(2,4-difluorophenyl)-N′- heptylurea as Acyl-CoA:cholesterol acyltransferase inhibitors
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Mono- and diphenylpyridazine ureido derivatives, structurally related to DuP 128, were synthesized and tested for their inhibitory activity against ACAT isolated from rat liver microsomes. Several compounds displayed ACAT inhibition in the micromolar range. The amino derivatives 4a-c were also tested against hACAT-1 and hACAT-2 isoforms. They retained the same trend shown in the previous assay. Modeling studies on representative terms were performed. Significant similarities between the geometrical features of the model DuP 128 and the most active pyridazine derivatives were observed.
- Gelain, Arianna,Bettinelli, Ilaria,Barlocco, Daniela,Kwon, Byoung-Mog,Jeong, Tae-Sook,Cho, Kyung-Hyun,Toma, Lucio
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p. 7708 - 7713
(2007/10/03)
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- Highly selective mono-substitution in Pd-catalyzed cross-coupling reactions of 3,6-dichloropyridazine with organozinc compounds
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Pd-catalyzed cross-coupling reactions of 3,6-dichloropyridazine (1) with benzyl, aryl, and alkyl organozinc compounds led to selective mono-substitution of one of the chlorine atoms. The subsequent cross-coupling of the resulting monochlorides with RZnCl afforded unsymmetrical 3,6-carbon-disubstituted pyridazines.
- Chekmarev, Dmitriy S.,Stepanov, Alexander E.,Kasatkin, Alexander N.
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p. 1303 - 1305
(2007/10/03)
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- Desymmetrization of dichloroazaheterocycles
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3,6-Dichloropyridizine 1a was converted in good yield into its mono-iodo derivative 1b when treated with a mixture of hydriodic acid and sodium iodide. Pure samples of the mono-iodo derivatives 2b, 3b and 4b could not be obtained from their corresponding dichlorinated precursors with these reagents. Compounds 1b and 4b underwent palladium catalysed Suzuki, Sonogashira and other coupling reactions.
- Goodman, Allan J.,Stanforth, Stephen P.,Tarbit, Brian
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p. 15067 - 15070
(2007/10/03)
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- 5-HT3 antagonists derived from aminopyridazine-type muscarinic M1 agonists
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A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 ± 0.5 A? between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 ± 0.03 A? of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC50 values for 5-HT3 receptor binding ([3H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([2SH] pirenzepine) layed over 10 000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist- like effects on those responsible for the slowly desensitizing components.
- Rival, Yveline,Hoffmann, Rémy,Didier, Bruno,Rybaltchenko, Volodymyr,Bourguignon, Jean-Jacques,Wermuth, Camille G.
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p. 311 - 317
(2007/10/03)
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- Diazines VII. A new synthetic route to the pyridazine antidepressant, minaprine using directed ortho metalation and Suzuki cross coupling reactions
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A new synthetic route has been developed for minaprine.The synthesis is based upon two reactions recently studied on pyridazine: metalation and cross coupling with transition metals.Some different routes have been tested starting from 3,6-dichloropyridazine.The best results were obtained by coupling phenylboronic acid with 3-chloro-6-methoxypyridazine then by metalating 3-methoxy-6-phenylpyridazine and reacting the lithio derivatives with methyl iodide. 3-Methoxy-4-methyl-6-phenylpyridazine was obtained.After hydrolysis of the ether moiety, chlorination and substitution by the amine, minaprine was obtained with an overall yield of 36percent.Keywords - pyridazine / metalation / cross-coupling
- Turck, A.,Ple, N.,Mojovic, L.,Queguiner, G.
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p. 488 - 492
(2007/10/02)
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- Synthesis and Structure-Activity Relationships of Series of Aminopyridazine Derivatives of γ-Aminobutyric Acid Acting as Selective GABA-A Antagonists
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We have recently shown that an aryloaminopyridazine derivarive of GABA, SR 95103 , is a selective and competitive GABA-A receptor antagonist.In order to further explore the structural requirements for GABA receptor affinity, we synthesized a series of 38 compounds by attaching various pyridazinic structures to GABA or GABA-like side chains.Most of the compounds displaced GABA from rat brain membranes.All the active compounds antagonized the GABA-elicited enhancement of diazepam binding, strongly suggesting that all these compounds are GABA-A receptor antagonists.None of the compounds that displaced GABA from rat brain membranes interacted with other GABA recognition sites (GABA-B receptor, GABA uptake binding site, glutamate decarboxylase, GABA-transaminase).They did not interact with the Cl- ionophore associated with the GABA-A receptor and did not interact with the benzodiazepine, strychnine, and glutamate binding sites.Thus these compounds appear to be specific GABA-A receptor antagonists.In terms of structure-activity, it can be concluded that a GABA moiety bearing a positive charge is necessary for optimal GABA-A receptor recognition.Additional binding sites are tolerated only if they are part of a charge-delocalized amidinic or guanidinic system.If this delocalization is achieved by linking a butyric acid moiety to the N(2) nitrogen of a 3-aminopyridazine, GABA-antagonistic character is produced.The highest potency (ca.250 times bicuculline) was observed when an aromatic ? system, bearing electron-donating substituents, was present on the 6-position of the pyridazine ring.
- Wermuth, Camille-Georges,Bourguignon, Jean-Jacques,Schlewer, Gilbert,Gies, Jean-Pierre,Schoenfelder, Angele,et al.
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p. 239 - 249
(2007/10/02)
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- QUANTITATIVE DETERMINATION OF THE ELECTRONIC EFFECTS OF 3- AND 4-PYRIDAZINYL GROUPS FROM NMR SPECTRAL DATA FOR ISOMERIC AMINOPHENYL- AND PHENYLPYRIDAZINES
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The previously unknown aminophenylpyridazines were synthesized.The inductive and resonance constants of 3- and 4-pyridazinyl groups were calculated on the basis of 1H and 13C NMR spectral data for isomeric aminophenyl- and phenylpyridazines in dimethyl sulfoxide (DMSO).
- Shkurko, O. P.,Kuznetsov, S. A.,Denisov, A. Yu.,Mamaev, V. P.
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p. 763 - 770
(2007/10/02)
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- CHLOROSULFONYL ISOCYANATE:AN UNUSUAL CHLORINATING AGENT
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The reaction of chlorosulfonyl isocyanate with 6-aryl-3(2H)pyridazinones yields unusually 3-chlorosubstituted pyridazines.
- Srinivasan, T. N.,Rao, K. Rama,Satur, P. B.
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p. 543 - 546
(2007/10/02)
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- Method of treating asthma
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A method of treating asthma in a warm-blooded animal using the compound 6-phenyl-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one.
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