- Solvent Polarity Predictably Tunes Spin Crossover T1/2 in Isomeric Iron(II) Pyrimidine Triazoles
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Two isomeric pyrimidine-based Rdpt-type triazole ligands were made: 4-(4-methylphenyl)-3-(2-pyrimidyl)-5-phenyl-4H-1,2,4-triazole (L2pyrimidine) and 4-(4-methylphenyl)-3-(4-pyrimidyl)-5-phenyl-4H-1,2,4-triazole (L4pyrimidine). When reacted with [FeII(pyridine)4(NCE)2], where E = S, Se, or BH3, two families of mononuclear iron(II) complexes are obtained, including six solvatomorphs, giving a total of 12 compounds: [FeII(L2pyrimidine)2(NCS)2] (1), [FeII(L2pyrimidine)2(NCSe)2] (2), 2·1.5H2O, [FeII(L2pyrimidine)2(NCBH3)2]·2CHCl3 (3·2CHCl3), 3 and 3·2H2O, [FeII(L4pyrimidine)2(NCS)2] (4), 4·H2O, [FeII(L4pyrimidine)2(NCSe)2] (5), 5·2CH3OH, 5·1.5H2O, and [FeII(L4pyrimidine)2(NCBH3)2]·2.5H2O (6·2.5H2O). Single-crystal X-ray diffraction reveals that the N6-coordinated iron(II) centers in 1, 2, 3·2CHCl3, 4, 5, and 5·2CH3OH have two bidentate triazole ligands equatorially bound and two axial NCE co-ligands trans-coordinated. All structures are high spin (HS) at 100 K, except 3·2CHCl3, which is low spin (LS). Solid-state magnetic measurements show that only 3·2CHCl3 (T1/2 above 400 K) and 5·1.5H2O (T1/2 = 110 K) undergo spin crossover (SCO); the others remain HS at 300-50 K. When 3·2CHCl3 is heated at 400 K it desorbs CHCl3 becoming 3, which remains HS at 400-50 K. UV-Vis studies in CH2Cl2, CHCl3, (CH3)2CO, CH3CN, and CH3NO2 solutions for the BH3 analogues 3 and 6 led to a 6:1 ratio of Lnpyrimidine/Fe(II) being employed for the solution studies. These revealed SCO activity in all five solvents, with T1/2 values for the 2-pyrimidine complex (247-396 K) that were consistently higher than for the 4-pyrimidine complex (216-367 K), regardless of solvent choice, consistent with the 2-pyrimidine ring providing a stronger ligand field than the 4-pyrimidine ring. Strong correlations of solvent polarity index with the T1/2 values in those solvents are observed for each complex, enabling predictable T1/2 tuning by up to 150 K. While this correlation is tantalizing, here it may also be reflecting solvent-dependent speciation - so future tests of this concept should employ more stable complexes. Differences between solid-state (ligand field; crystal packing; solvent content) and solution (ligand field; solvation; speciation) effects on SCO are highlighted.
- Rodríguez-Jiménez, Santiago,Barltrop, Alexis S.,White, Nicholas G.,Feltham, Humphrey L. C.,Brooker, Sally
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Read Online
- Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
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A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
- Okawa, Tomohiro,Aramaki, Yoshio,Yamamoto, Mitsuo,Kobayashi, Toshitake,Fukumoto, Shoji,Toyoda, Yukio,Henta, Tsutomu,Hata, Akito,Ikeda, Shota,Kaneko, Manami,Hoffman, Isaac D.,Sang, Bi-Ching,Zou, Hua,Kawamoto, Tetsuji
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p. 6942 - 6990
(2017/09/07)
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- Synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents
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The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large number of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We determined that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar minimum inhibitory concentrations being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel antitubercular agents.
- Kesicki, Edward A.,Bailey, Mai A.,Ovechkina, Yulia,Early, Julie V.,Alling, Torey,Bowman, Julie,Zuniga, Edison S.,Dalai, Suryakanta,Kumar, Naresh,Masquelin, Thierry,Hipskind, Philip A.,Odingo, Joshua O.,Parish, Tanya
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- Electron-deficient heteroarenium salts: An organocatalytic tool for activation of hydrogen peroxide in oxidations
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A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pKR+ values (pKR+ red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.
- ?turala, Ji?í,Bohá?ová, Soňa,Chudoba, Josef,Metelková, Radka,Cibulka, Radek
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p. 2676 - 2699
(2015/03/18)
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- Pyruvamide Compounds as Inhibitors of Dust Mite Group 1 Peptidase Allergen and Their Use
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The present invention pertains generally to the field of therapeutic compounds and more specifically to certain pyruvamide compounds of the formula (X) (for convenience, collectively referred to herein as “PVA compounds”), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.
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- NON-PEPTIDYL, POTENT, AND SELECTIVE MU OPIOID RECEPTOR ANTAGONISTS
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Selective, non-peptide antagonists of the ma opioid receptor { MOR) and methods of their use are provided. The antagonists may be used, for example, to identify MOR agonists in competitive binding assays, and to treat conditions related to addiction in which MOR is involved, e.g. heroin, prescription drug and alcohol addiction.
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Page/Page column 61
(2010/08/08)
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- PYRIMIDONE COMPOUNDS AS GSK-3 INHIBITORS
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The invention relates to pyrimidone derivatives I having activity as GSK-3 inhibitors. The invention further relates to pharmaceutical compositions comprising such derivatives and uses thereof in treating certain disorders. Formula (I):
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Page/Page column 21
(2008/06/13)
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- SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
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This invention relates to novel 2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition and treating diseases associated with phosphotidylinositol-3-kinase (PI3K) activity, in particular treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.
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Page/Page column 59
(2008/12/06)
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- Facile, one-step production of niacin (vitamin B3) and other nitrogen-containing pharmaceutical chemicals with a single-site heterogeneous catalyst
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Niacin (3-picolinic acid), which is extensively used as vitamin B 3 in foodstuffs and as a cholesterol-lowering agent, along with other oxygenated products of the picolines, 4-methylquinoline, and a variety of pyrimidines and pyridazines, may be produced in a single-step, environmentally benign fashion by combining single-site, open-structure, heterogeneous catalysts witha solid source of active oxygen, namely acetyl peroxyborate (APB), in the absence of an organic solvent. The high activities, selectivities, and the relatively mild conditions employed with this single-site heterogeneous catalyst, coupled with ease of transport, storage, and stability of the solid oxidant, augurs well for the future use of APB in conjunction with other open-structure, single-site catalysts for fine-chemical, pharmaceutical, and agrochemical applications.
- Raja, Robert,Thomas, John Meurig,Greenhill-Hooper, Michael,Ley, Steven V.,Almeida Paz, Filipe A.
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experimental part
p. 2340 - 2348
(2009/04/11)
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- ARYL SULFONAMIDES
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Compounds are provided that act as potent antagonists of the CCR9 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, (I) a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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- Improved oxidation of active methyl group of N-heteroaromatic compounds by selenium dioxide in the presence of tert-butyl hydroperoxide
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The oxidation of active methyl group of N-heteroaromatic compounds including both of bicyclic and monocyclic compounds using SeO2 was considerably improved in the presence of tert-butyl hydroperoxde in dioxane to give the corresponding aldehyde or carboxylic acid in the moderate to good yields. The present oxidation proceeds more mildly and more selectively to form aldehyde rather than carboxylic acid, compared with conventional SeO2 oxidation without tert-butyl hydroperoxide.
- Tagawa, Yoshinobu,Yamashita, Katsuya,Higuchi, Yoshitaka,Goto, Yoshinobu
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p. 953 - 957
(2007/10/03)
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- The chemistry of [1,2,3]triazolo[1,5-c]pyrimidine
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Reactions of [1,2,3]triazolo[1,5-c]pyrimidine 2 with some electrophiles and nucleophiles are reported. Triazole ring opening and loss of nitrogen is the principal reaction with electrophiles. With strong acids protonation on N6 competes successfully. Derivatives in which the pyrimidine ring has been opened are obtained in reactions with nucleophiles. No stable simple substitution compounds were found.
- Abarca,Ballesteros,Chadlaoui,Miralles,Murillo,Colonna
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p. 10111 - 10117
(2007/10/03)
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- AUTOOXIDATION OF METHYLHETEROCYCLES UNDER PHASE TRANSFER CATALYSIS CONDITIONS
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The autooxidation of methyl- and dimethyl-substituted N-, S-, and O-heterocyclic compound derivatives has been studied in 1,2-dimethoxyethane-t-BuOK in the presence of 18-crown-6.Mono- and dicarboxylic acid derivatives of pyrazine, pyridine, pyrimidine, and thiophene have been synthesized.
- Iovel', I. G.,Gol'dberg, Yu. Sh.,Gaukhman, A. P.,Zolotoyabko, R. M.,Shimanskaya, M. V.
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p. 768 - 771
(2007/10/02)
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- Process for the preparation of 7-amino and 7-substituted amino-desacetoxycephalosporins
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An improved process is disclosed for the preparation of 7-amino and 7-substituted amino-desacetoxycephalosporins in which the corresponding 6-substituted amino penicillin sulphoxide is heated in the presence of an acidic substance which causes expansion of the penam ring in the reactant to the Δ3 cephem ring in the product in the presence of a silicon containing compound. The process comprises adding sulphamide or a silylsulphamide or a silylsulphamoyl to the reaction or utilizing a silylsulphamide or silylsulphamoyl as the silicon containing compound.
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