- Imidazole- and benzimidazole-based inhibitors of the kinase IspE: Targeting the substrate-binding site and the triphosphate-binding loop of the ATP site
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The enzymes of the mevalonate-independent biosynthetic pathway to isoprenoids are attractive targets for the development of new drug candidates, in particular against malaria and tuberculosis, because they are present in major human pathogens but not in humans. Herein, the structure-based design, synthesis, and biological evaluation of a series of inhibitors featuring a central imidazole or benzimidazole scaffold for the kinase IspE from E. coli, a model for the corresponding malarial enzyme, are described. Optimization of the binding preferences of the hydrophobic sub-pocket at the substrate-binding site allowed IC50 values in the lower micromolar range to be reached. Structure-activity relationship studies using a 1,2-disubstituted imidazole central core revealed that alicyclic moieties fit the sub-pocket better than acyclic aliphatic and aromatic residues. The phosphate-binding region in the ATP-binding site of IspE, a neutral glycine-rich loop, was addressed for the first time by an additional vector attached to the central core. Polar functional groups, such as trifluoromethyl or nitriles, were introduced to undergo orthogonal dipolar interactions with the amide groups in the loop. Alternatively, small hydrogen-bond-accepting heterocyclic residues, capable of binding to the convergent NH groups in the loop, were explored. The biological data showed slightly improved inhibitory potency in some cases and confirmed the challenges in addressing, with gain in binding affinity, the highly water-exposed sections of enzyme active sites, such as the glycine-rich loop of IspE. Inhibitors of the kinase E. coli IspE, an enzyme involved in the synthesis of isoprenoids and a model for IspE from P. falciparum, were developed. Decorated imidazole- and benzimidazole-based scaffolds address the cytidine-binding pocket, the hydrophobic sub-pocket, and the phosphate-binding region in the active site. In vitro activities in the micromolar IC 50-range were measured. Copyright
- Mombelli, Paolo,Le Chapelain, Camille,Munzinger, Noah,Joliat, Evelyne,Illarionov, Boris,Schweizer, W. Bernd,Hirsch, Anna K. H.,Fischer, Markus,Bacher, Adelbert,Diederich, Francois
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supporting information
p. 1068 - 1079
(2013/03/28)
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- Synthesis, structure-activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1
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A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.
- Sifferlen, Thierry,Koberstein, Ralf,Cottreel, Emmanuelle,Boller, Amandine,Weller, Thomas,Gatfield, John,Brisbare-Roch, Catherine,Jenck, Francois,Boss, Christoph
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p. 2212 - 2216
(2013/04/23)
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- Ligand modification of cyclometalated ruthenium complexes in the aerobic oxidative dehydrogenation of imidazolines
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New cyclometalated ruthenium(III) complexes bearing 2-phenylpyridine derivatives were synthesized and characterized. Chemical modification of the cyclometalating ligand affected its σ-donor character and resulted in regulation of the redox potential of the ruthenium metal center, which was elucidated by X-ray crystallography and cyclic voltammetry. The increase in the electron-donating ability of the cyclometalating ligand improved the catalytic activity of the ruthenium complexes in the aerobic oxidative dehydrogenation of 2-phenylimidazoline, and enabled the catalytic dehydrogenation of 2-phenylimidazoline in air at room temperature. The effect of the ligand structure on the catalytic activity was also elucidated by density functional theory (DFT) calculations and titration experiments.
- Aiki, Shota,Kijima, Yuhei,Kuwabara, Junpei,Taketoshi, Ayako,Koizumi, Take-Aki,Akine, Shigehisa,Kanbara, Takaki
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p. 812 - 816
(2013/07/25)
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- Structure and synthesis of 6-(substituted-imidazol-1-yl)purines: Versatile substrates for regiospecific alkylation and glycosylation at N9
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X-ray crystal structures of several 6-(azolyl)purine base and nucleoside derivatives show essentially coplanar conformations of the purine and appended 6-(azolyl) rings. However, the planes of the purine and imidazole rings are twisted ~57° in a 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine nucleoside, and a twist angle of ~61° was measured between the planes of the purine and pyrrole rings in the structure of a 6-(2,5-dimethylpyrrol-1-yl) purine nucleoside derivative. Shielding "above" N7 of the purine ring by a proximal C-H on the 6-azolyl moiety is apparent with the coplanar compounds, but this effect is diminished in those without coplanarity. Syntheses of 6-(azolyl)purines from both base and nucleoside starting materials are described. Treatment of 2,6-dichloropurine with imidazole gave 2-chloro-6-(imidazol-1-yl)purine. Modified Appel reactions at C6 of trityl-protected hypoxanthine and guanine derivatives followed by detritylation gave 6-(imidazol-1-yl)- and 2-amino-6-(imidazol-1-yl)purines. Imidazole was introduced at C6 of 2′,3′,5′-tri-O-acetylinosine by a modified Appel reaction, and solvolysis of the glycosyl linkage gave 6-(imidazol-1-yl)purine. Guanosine triacetate was transformed into the protected 2,6-dichloropurine nucleoside, which was subjected to SNAr displacement with imidazoles at C6 followed by glycosyl solvolysis to provide 2-chloro-6-(substituted-imidazol-1-yl)purines. Potential applications of these purine derivatives are outlined.
- Zhong, Minghong,Nowak, Ireneusz,Cannon, John F.,Robins, Morris J.
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p. 4216 - 4221
(2007/10/03)
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- METHODS FOR SELECTIVE N-9 GLYCOSYLATION OF PURINES
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A process for providing regiospecific and highly stereoselective synthesis of 9-β anomeric purine nucleoside analogs is described. The introduction of the sugar moiety on to 6-(azolyl)-substituted purine bases is performed so that highly stereoselective formation of the β anomers of only the 9 position regioisomers of the purine nucleoside analogs (either D or L enantiomers) is obtained. This regiospecific and stereoselective introduction of the sugar moiety allows the synthesis of nucleoside analogs, and in particular 2'-deoxy, 3'-deoxy, 2'-deoxy-2'-halo-arabino and 2',3'-dideoxy-2'-halo-threo purine nucleoside analogs, in high yields without formation of the 7-positional regioisomers. Processes for providing novel 6-(azolyl)purines for the regiospecific and highly stereoselective synthesis of 9-β anomeric purine nucleoside analogs are described. The compounds are drugs or intermediates to drugs.
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Page/Page column 47-48
(2010/11/25)
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- Tetrasubstituted imidazoles
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A compound of the formula STR1 wherein the substituents are defined in the specification useful for the treatment of cardiovascular disorders.
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- Method of preventing abnormal stimulation of AT1 and AT2 receptors
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Products of formula (1), wherein R1 is particularly STR1 alkyl, alkylthio or alkoxy; R2 is particularly halogen, --S--R, --O--R or --C(OH)(R)--COOH, where R is alkyl or alkenyl; R3 is particularly carboxy, acyl, halogen, alkyl, alkenyl or alkylthio; and R4 is particularly --(CH2)m1 --COOR4, --(CH2)m1 --CONHR14, --(CH2)m1 --CN, --SO2 --NH--SO2 --R14, 13 NH--SO2 --R14, --PO3 R14, or --NH--SO2 --CF3, where m1 is 0-4 and R14 is hydrogen, alkyl or alkenyl; are useful for preparing pharmaceutical compositions for treating disorders resulting from abnormal stimulation of angiotensin II receptors AT1 and AT2.
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- 1H-IMIDAZOLE PREPARATION VIA PERMANGANATE DEHYDROGENATION OF 2-IMIDAZOLINES
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Permanganate and manganate ions were evaluated as dehydrogenating agents in the conversion of 2-substituted 2-imidazolines into the corresponding 2-substituted imidazoles.It was found that permanganate ion in dry dioxane efficiently performs this transformation rendering this method competitive with related procedures.
- Campos, Elena Ma.,Jimenez, Rogelio,Martinez, Flor,Salgado, Hector
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p. 841 - 850
(2007/10/02)
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- Indole- and benzimidazole-substituted imidazole derivatives
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Novel compounds having the formula STR1 where X R1, R2, R3, R4, R5 and R6 are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore for example, as antihypertensive agents.
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- N-(Heterocycl ic-alkyl)-9-xanthenylamines
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The compounds are N-(imidazolylalkyl, imidazolinylalkyl and tetrahydropyrimidylalkyl)-9-xanthenylamines which have gastric acid secretion inhibitory activity.
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