- PH-metric chemical speciation modeling and studies of in vitro antidiabetic effects of bis[(imidazolyl)carboxylato]oxidovanadium(IV) complexes
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A range of bidentate N,O-donor ligands of the imidazolyl-carboxylate moiety, which partially mimic naturally occurring bioligands, were prepared and reacted with the oxidovanadium(IV) ion to form the corresponding bis-coordinated oxidovanadium(IV) complexes. The aqueous pH-metric chemical speciation was investigated using glass electrode potentiometry, which allowed for the determination of protonation and stability constants of the ligands and complexes, respectively. The species distribution diagrams generated from this information gave evidence that the bis[(imidazolyl)carboxylato]oxovanadium(IV) complexes possess a broad pH-metric stability. The complexes improved glucose uptake in cell cultures using 3T3-L1 adipocytes, C2C12 muscle cells and Chang liver cells. The PTP inhibition studies indicated that the mechanism underlying insulin-stimulated glucose uptake was possibly via the protein tyrosine phosphorylation through the inhibition of the protein tyrosine phosphatase 1B (PTP 1B). The vanadium compounds also demonstrated the inhibition of D-dimer formation, suggesting that these compounds could potentially relieve a hypercoagulative state in diabetic patients.
- Gundhla, Isaac Z.,Walmsley, Ryan S.,Ugirinema, Vital,Mnonopi, Nandipha O.,Hosten, Eric,Betz, Richard,Frost, Carminita L.,Tshentu, Zenixole R.
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- New blue phosphorescent heteroleptic Ir(iii) complexes with imidazole- and: N -methylimidazole carboxylates as ancillary ligands
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Imidazole- and N-methylimidazole carboxylate have been introduced to serve as ancillary ligands in heteroleptic Ir(iii) complexes containing 2-phenylpyridine-based main ligands, with consideration of the frontier orbital energy levels. Complexes Ir1-Ir4 were synthesized and found to have LUMO levels higher than that of the corresponding Ir(iii) complex containing pyridyl carboxylate. All the synthesized Ir(iii) complexes exhibited blue phosphorescence emission maxima in the region of 465-467 nm at room temperature. Phosphorescent quantum efficiencies were increased by a factor of 1.8-6.7 by blocking the intermolecular hydrogen bonding between the imidazole carboxylate ligands of neighboring Ir(iii) complexes, which was achieved by N-methylation of the imidazole carboxylate ancillary ligand. The organic light-emitting diodes fabricated using Ir3 and Ir4 as dopant materials in the emissive layers were found to emit blue emission with peaks at 469 and 471 nm and maximum external quantum efficiencies of 20.0 and 22.4%, respectively. Moreover, all the fabricated devices with Ir3 and Ir4 exhibited low efficiency roll-off, indicating excellent stability of the materials.
- Chae, Eun Ah,Chung, Won Jae,Hwang, Do-Hoon,Jang, Jae-Ho,Lee, Jun Yeob,Park, Hea Jung,Seo, Hye Won,Yoon, Ung Chan
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- Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
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Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
- Yan, Yu-Hang,Li, Wenfang,Chen, Wei,Li, Chao,Zhu, Kai-Rong,Deng, Ji,Dai, Qing-Qing,Yang, Ling-Ling,Wang, Zhenling,Li, Guo-Bo
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- Oxidation of imidazole- and pyrazole-derived aldehydes by plant aldehyde dehydrogenases from the family 2 and 10
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Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective Km values were in the range of 10–2000 μmol l?1; the kcat values appeared mostly between 0.1 and 1.0 s?1. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.
- Fr?mmel, Jan,Kon?itíková, Radka,Kope?ny, David,Soural, Miroslav,?ebela, Marek
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p. 194 - 201
(2019/03/06)
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- 4-alkyl-imidazole-2-carboxylic acid synthesizing method
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The invention provides a method for synthesizing 4-alkylimidazole-2-carboxylic acid I. The method comprises the steps of firstly, reacting 2-alkyl-imidazole II as a raw material with BnX in the presence of a base to generate a mixture of a pair of position isomers IIIa and IIIb; secondly, on the premise that the mixture is not separated, reacting the mixture with halogenated formate (i.e., XCOOR2) in the presence of a base to generate a pair of corresponding isomers IVa and IVb; thirdly, hydrogenating to remove a benzyl group V in the presence of a hydrogenation catalyst; and fourthly, in the presence of a base, hydrolyzing to obtain the desired product 4-alkylimidazole-2-carboxylic acid I. The reaction route is shown in the specification, wherein R1 is selected from hydrogen atom and lower alkyl groups such as methyl and ethyl and R2 is selected from C1-C6 alkyl, C1-C6 alkoxy substituted group, a phenyl group or a benzyl group. The method disclosed by the invention has ingenious concept, since an inexpensive reagent is used in the respective step, and the yield of each step is high, the final target product 4-alkylimidazole-2-carboxylic acid I can be obtained in efficiency, convenience and low cost.
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Paragraph 0039; 0051; 0052; 0059; 0060
(2017/01/26)
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- PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS
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New pyrrolotriazinone derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).
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Page/Page column 118
(2012/11/13)
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- Pyrrolotriazinone derivatives as PI3K inhibitors
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New pyrrolotriazinone derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks)
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(2012/11/13)
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- IMIDAZOLE CARBONYL COMPOUND
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To develop an antibiotic having a novel mechanism of action, the present inventors have searched for a compound that has weak cytotoxicity, the physical property of high solubility in water, the effect of inhibiting both DNA gyrase GyrB and topoisomerase IV ParE subunits, and sufficient antibacterial activity. As a result, the present inventors have completed the present invention by finding that a compound of the present invention represented by the general formula (1), a pharmacologically acceptable salt thereof, and a prodrug thereof have desirable properties. The present invention provides a pharmaceutical composition (particularly, a preventive or therapeutic composition for infectious disease) comprising a compound represented by the formula (1), a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient.
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Page/Page column 30
(2010/09/17)
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- CORTICOID-17,21-DICARBOXYLIC ESTERS AND CORTICOSTEROID 17-CARBOXYLIC ESTER 21-CARBONIC ESTERS, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICALS CONTAINING THESE COMPOUNDS
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Corticoid 17,21-dicarboxylic esters and corticosteroid 17-carboxylic ester 21-carbonic esters, processes for their preparation and pharmaceuticals containing these compounds Corticoid 17,21-dicarboxylic esters and corticoid 17-carboxylic ester 21-carbonic esters of the formula I are described, in which A is CHOH and CHCl, CH2, C═O or 9(11) double bond; Y is H, F or Cl; Z is H, F or methyl; R(1) is aryl or hetaryl; R(2) is alkyl and R(3) is H or methyl. They are obtained, inter alia, by reacting a compound of the formula II, in which R(5) is OH, with an activated carboxylic acid of the formula III, R(6)—CO—(O)n[(C1-C4)-alkyl]m-R(1) ??III. They have a very strong local and topical antiinflammatory action and exhibit a very good ratio of local to systemic antiinflammatory effects. They are used, inter alia, as agents for treating inflammatory dermatoses.
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- Corticosteroid 17-alkyl carbonate 21-[0]-carboxylic and carbonic esters, and pharmaceuticals containing these compounds
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Corticoid 17-alkyl carbonate 21-carboxylic and carbonic esters of the formula I STR1 are described in which A is CHOH and CHCl, CH2, C=O or 9(11) double bond; Y is H, F or Cl; Z is H, F or CH3 ; R(1) is aryl or hetaryl; n and m are zero or 1; R(2) is alkyl or --(CH2)2 --OCH3 ; R(3) is H or methyl. They are obtained by reacting a compound of the formula II, STR2 in which R(5) is OH, with an activated carboxylic acid of the formula III, The compounds I have a very strong local and topical antiinflammatory action and exhibit a very good ratio of local to systemic antiinflammatory effects, which ratio is often markedly superior to that of analogous corticoid 17-alkyl carbonate 21-esters which do not carry any aryl or heteraryl group in the 21-ester radical.
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- Imidazole compound and process for preparing the same
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An imidazole compound is disclosed, which is represented by formula (I): STR1 wherein: X represents a --COOT group, in which T represents a hydrogen atom, an alkyl group, a benzyl group, or a phenyl group; or a --CONH2 group, Y represents a hydrogen atom, a chlorine atom, or a bromine atom, Z represents an alkyl group containing from 2 to 6 carbon atoms, which may be substituted with one or more halogen atoms; or a phenyl group which may be substituted with one or more halogen atoms or alkyl groups, and Q represents a hydrogen atom; an --SO2 R1 group, in which R1 represents an alkyl group, a dialkylamino group, or a phenyl group which may be substituted with one or more alkyl groups; or a --CH(R2)(R3) group, in which R2 represents a hydrogen atom, a methyl group, or an alkoxy group, and R3 represents an alkoxy group, an --OCH2 CH2 Si (CH3) group, or a phenyl group which may be substituted with one or more alkyl groups or alkoxy groups, provided that when Y and Q each represents a hydrogen atom and Z represents a phenyl group, X represents a group other than a --COOH-phenyl group, and a --CONH2 group; and that when Y and Q each represents a hydrogen atom and Z represents an n--C5 H11 group, X represents a group other than a --COOH group and a --COOC2 H5 group. Processes for preparing imidazole compounds are also disclosed. The imidazole compounds are useful as an intermediate for production of biocides for controlling harmful organisms in the agricultural and horticultural areas, or medical and pharmaceutical fungicides.
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- Plant growth regulant compositions
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The imidazole-2-carboxylic acid amides of the general formula STR1 in which R represents alkyl, have powerful growth-regulating properties. The invention provides a method of regulating the growth of plants, which comprises applying to the plants, or to a habitat thereof, a compound of the formula (I) alone or in the form of a composition containing as active ingredient a compound of the formula (I) in admixture with a diluent or carrier.
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- Syntheses and Reactions of Some 4,5-Dihaloimidazole-2-carboxylic Acid Derivatives
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The preparation of 5H,10H-diimidazopyrazine-5,10-dione (2a) and its 2,3,7,8-tetrabromo- and 2,3,7,8-tetrachloro- analogs (2b and 2c, respectively) is reported.These dimers, when allowed to react with various anilines, afford imidazole-2-carboxamides (3a-c).
- Dirlam, John P.,James, Richard B.,Shoop, Eleanor V.
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p. 409 - 411
(2007/10/02)
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- An Easily Introduced and Removed Protecting Group for Imidazole Nitrogen: A Convenient Route to 2-Substituted Imidazoles
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Orthoamides (3-5) prepared from imidazoles and triethyl or trimethyl orthoformate are rapidly metalated at -40 deg C in THF or ether to give the corresponding 2-lithio anion which reacts with a variety of electrophiles.The dialkoxymethyl protecting group is readily hydrolyzed under neutral or acidic conditions at room temperature, giving the 2-substituted 1H-imidazole 1 (R = H, X = COOH, n-C4H9, COCH3, CHOHC6H5, C(CH3)OH-2-pyridyl,9-hydroxyfluorenyl, 1-hydroxycyclohex-2-enyl, C(OH)(C6H5)2; R = CH3, R' = H, X = CHO) and the tris(2-imidazolyl)phosphines (R = H, CH3, CH(CH3)2).A mechanism for the deprotection of 3 is proposed.
- Curtis, N.J.,Brown, R.S.
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p. 4038 - 4040
(2007/10/02)
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