- Mass Spectrometry of Nitroazoles. 3-Ortho Effects: The loss of OH. and H2O from Methyl Substituted Nitrodiazoles
-
Methyl substituted nitrodiazoles which have the substituents at adjacent positions in the ring are subject to several ortho effects.Deuterium labelling of the methyl group and the mobile N-bonded hydrogen show that the loss of OH. originates from the substituents.In some cases the N-bonded hydrogen atom participates also in the loss of OH. and of H2O.
- Luijten, W. C. M. M.,Thuijl, J. van
-
-
Read Online
- Transformations of 3-nitropyridin-4(1H)-one and 1-Methyl-3-nitropyridin- 4(1H)-one in reaction with hydrazine
-
Hydrazinolysis of 3-nitropyridin-4(1H)-one and its N-methyl derivative leads to the formation of 1-(1H-pyrazol-3-yl)ethanone hydrazone whose structure was confirmed by independent synthesis from authentic 3-acetyl-1H-pyrazole and comparison of the IR and
- Smolyar
-
-
Read Online
- Synthesis and evaluation of original bioisosteres of bacterial type IIA topoisomerases inhibitors
-
A recently discovered series of inhibitors of the ATPase function of bacterial type IIA topoisomerases featuring a carboxypyrrole component led us to attempt to replace this group with a potentially bioisosteric carboxypyrazole. Accordingly, synthetic pathways to 2-(4-(1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids or 2-(4-(N-methyl-1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids featuring an array of substituents on the pyrazole ring were explored. Unfortunately, none of the analogues made were effective on the ATPase function of Mycobacterium tuberculosis gyrase as well on the DNA supercoiling activity of the whole gyrase of M. tuberculosis and Escherichia coli. However, this work is still providing original insights in chemistry as well as in the structure-activity relationships of this series of inhibitors.
- Petrella, Stéphanie,Aubry, Alexandra,Janvier, Geneviève,Coutant, Eloi P.,Cartier, Alex,Dao, Thuy-Ha,Bonhomme, Frédéric J.,Motreff, Laurence,Pissis, Cédric,Bizet, Chantal,Clermont, Dominique,Begaud, Evelyne,Retailleau, Pascal,Munier-Lehmann, Hélène,Capton, Estelle,Mayer, Claudine,Janin, Yves L.
-
-
Read Online
- Oxidation of imidazole- and pyrazole-derived aldehydes by plant aldehyde dehydrogenases from the family 2 and 10
-
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
-
p. 194 - 201
(2019/03/06)
-
- Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors
-
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis-Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.
- Janssen, Antonius P.A.,Van Hengst, Jacob M.A.,Béquignon, Olivier J.M.,Deng, Hui,Van Westen, Gerard J.P.,Van Der Stelt, Mario
-
p. 7910 - 7922
(2019/10/11)
-
- Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design
-
Several bacteria rely on the reductive sulphur assimilation pathway, absent in mammals, to synthesise cysteine. Reduction of virulence and decrease in antibiotic resistance have already been associated with mutations on the genes that codify cysteine biosynthetic enzymes. Therefore, inhibition of cysteine biosynthesis has emerged as a promising strategy to find new potential agents for the treatment of bacterial infection. Following our previous efforts to explore OASS inhibition and to expand and diversify our library, a scaffold hopping approach was carried out, with the aim of identifying a novel fragment for further development. This novel chemical tool, endowed with favourable pharmacological characteristics, was successfully developed, and a preliminary Structure–Activity Relationship investigation was carried out.
- Magalh?es, Joana,Franko, Nina,Annunziato, Giannamaria,Welch, Martin,Dolan, Stephen K.,Bruno, Agostino,Mozzarelli, Andrea,Armao, Stefano,Jirgensons, Aigars,Pieroni, Marco,Costantino, Gabriele,Campanini, Barbara
-
p. 1444 - 1452
(2018/09/25)
-
- Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors
-
A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.
- Lee, Eun,An, Ying,Kwon, Junhee,Kim, Keun Il,Jeon, Raok
-
p. 3614 - 3622
(2017/06/13)
-
- Synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents
-
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
-
-
- ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
-
Compounds of formula (I) or (II) wherein Rx, Rz, R9, R10, R14, R14′, R15, R15′, A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
- -
-
Page/Page column
(2015/05/06)
-
- Pyrazole-3/5-carboxylic acids from 3/5-trifluoromethyl NH-pyrazoles
-
We report here the transformation of 3/5-trifluoromethylpyrazoles derivative into the corresponding NH-pyrazole-3/5-carboxylic acids. Moreover, from 4- or 5-iodinated-3/5-trifluoromethylpyrazoles building blocks and the use of Suzuki-Miyaura or Negishi reactions followed by the trifluoromethyl hydrolysis, we illustrate short and original accesses to many series of NH-pyrazole-3/5-carboxylic acids otherwise difficult to prepare.
- Ermolenko, Mikhail S.,Guillou, Sandrine,Janin, Yves L.
-
p. 257 - 263
(2013/01/15)
-
- 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
-
The present invention relates to novel 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl-amine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease or dementia associated with beta-amyloid.
- -
-
Paragraph 0099; 0100
(2013/07/31)
-
- Preparations of 4-substituted 3-carboxypyrazoles
-
The scopes of three synthetic methods reported for the preparation of an array of 3-pyrazolecarboxylates featuring substituents on position 4 were investigated. The first one is based on the potassium permanganate oxidation of methylpyrazoles. The second starts with the condensation between DMF dimethylacetal and ethyl pyruvate and is followed by the addition of hydrazine hydrochloride. The last one makes use of the cycloaddition of diazomethane on acrylate esters followed by a bromine-based oxidative rearrangement into 4-substituted 3-pyrazole esters.
- Janin, Yves L.
-
p. 1410 - 1414
(2014/01/06)
-
- 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
-
The present invention relates to novel 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl- aminederivativesas inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretaseis involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associatedwith stroke, dementia associated with Parkinson's disease or dementia associated with beta- amyloid.
- -
-
Page/Page column 32
(2012/04/10)
-
- ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
-
Compounds of formula (I) wherein Rx, Rz, R9, R10, R14, R14', R15, R15', A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
- -
-
Page/Page column 62
(2012/11/07)
-
- IMIDAZOPYRIDINE DERIVATIVES AS JAK INHIBITORS
-
New imidazopyridine 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 Janus Kinases (JAK).
- -
-
Page/Page column 131-132
(2011/07/09)
-
- Imidazopyridine derivatives as JAK inhibitors
-
New imidazopyridine 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 Janus Kinases (JAK).
- -
-
Paragraph 0215; 0216
(2013/03/26)
-
- N-Benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors
-
A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse.
- Atkinson, Karen A.,Beretta, Elena E.,Brown, Janice A.,Castrodad, Mayda,Chen, Yue,Cosgrove, Judith M.,Du, Ping,Litchfield, John,Makowski, Michael,Martin, Kelly,McLellan, Thomas J.,Neagu, Constantin,Perry, David A.,Piotrowski, David W.,Steppan, Claire M.,Trilles, Richard
-
scheme or table
p. 1621 - 1625
(2011/05/05)
-
- Cyclizations of monocyclic 5-nitropyridin-2(1H)-ones
-
Reactions of 5-nitropyridin-2(1H)-one and its N-methyl derivative with hydrazine hydrate led to the formation of (1H-pyrazol-3-yl) acetohydrazide. Under analogous conditions, 1,3-dimethyl-5-nitropyridin2(1H)-one gave rise to 2-(1H-pyrazol-3-yl)propionohyd
- Smolyar,Yutilov
-
experimental part
p. 1205 - 1210
(2009/08/07)
-
- Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity
-
One of the possible mechanisms of antiviral action of ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, 1) is the accumulation of mutations in viral genomic RNA. The ambiguous incorporation of 5′-triphosphate of ribavirin (RTP, 8) by a viral RNA-dependent RNA polymerase (RdRp) is a key step of the mutation induction. We synthesized three ribavirin analogues that possess hydrophobic groups, 4-iodo-1-β-D- ribofuranosylpyrazole-3-carboxamide (7a), 4-propynyl-1-β-D- ribofuranosylpyrazole-3-carboxamide (7b), and 4-phenylethynyl-1-β-D- ribofuranosylpyrazole-3-carboxamide (7c), and the corresponding triphosphates (9a, 9b, and 9c, respectively). Steady-state kinetics analysis of the incorporation of these triphosphate analogues by a poliovirus RdRp, 3D pol, revealed that while the incorporation efficiency of 9a was comparable to RTP, 9b and 9c showed lower efficiency than RTP. Antipolioviral activity of 7a and 7b was much more moderate than ribavirin, and 7c showed no antipolioviral activity. Effects of substituting groups on the incorporation efficiency by 3Dpol and a strategy for a rational design of more active ribavirin analogues are discussed.
- Moriyama, Kei,Suzuki, Tetsuya,Negishi, Kazuo,Graci, Jason D.,Thompson, Corinne N.,Cameron, Craig E.,Watanabe, Masahiko
-
p. 159 - 166
(2008/09/18)
-
- PYRAZOLES USEFUL IN THE TREATMENT OF INFLAMMATION
-
There is provided compounds of formula (I), wherein R1, R2, X1, X2 and n have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.
- -
-
Page/Page column 54
(2008/06/13)
-
- PYRAZOLE COMPOUNDS USEFUL IN THE TREATMENT OF INFLAMMATION
-
There is provided compounds of formula (I), wherein R1, R2, Ra and Rb have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.
- -
-
Page/Page column 71
(2010/10/20)
-
- NOVEL FUSED HETEROCYCLES AND USES THEREOF
-
This invention relates to novel compounds having the Formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment or prophylaxis of H. pylori infection.
- -
-
Page/Page column 103
(2010/02/14)
-
- PYRAZOLE COMPOUNDS USEFUL IN THE TREATMENT OF INFLAMMATION
-
There is provided a compound of formula (I), wherein R1, R2, R3, X and Y have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.
- -
-
-
- 4-[(4-(CARBOXYETHYL) PIPERIDINYL) METHYL] PYRROLIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
-
3-Substituted pyrrolidines having a 4-carboxypiperidinylmethyl substituent on the 4-position of the ring are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
- -
-
-
- 4(SPIROPIPERIDINYL)METHYL SUBSTITUTED PYRROLIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
-
3-Substituted pyrrolidines having a spiropiperidinylmethyl substituent on the 4-position of the ring are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
- -
-
-
- Lanthanide podates with programmed intermolecular interactions: Luminescence enhancement through association with cyclodextrins and unusually large relaxivity of the gadolinium self-aggregates
-
The synthesis of the phenyl anchored podand H4L1 fitted with four 3-carboxylate pyrazole arms and programmed for intermolecular interactions is reported, and its protonation constants are determined. Interaction with Ln3+ ions (Ln = La, Eu, Lu) in dilute aqueous solutions leads to complexes with 1:1 and 1:2 metal-ligand stoichiometry. The stability constants are in the range log β110 = 12.7-13.5 and log β120 = 22.5-23.8 (pLn values in the range 9-10). The podates display a fair sensitization of the metal-centered luminescence with an absolute quantum yield of 5% in case of TbIII. The average numbers of water molecules coordinated to the LnIII ion amount to 3.8 and 4.9 for the 1:1 Eu and Tb podates, respectively, as determined by lifetime measurements. The addition of β- and γ-cyclodextrins to the 1:1 podates results in a strong association with the host, mainly through the phenyl anchor (Ln = Tb, log K11 = 5-6 depending on the cyclodextrin) and, for the Tb complex, to a large increase in luminescence intensity at physiological pH. Self-aggregation of the podates occurs at concentration larger than 3 x 10-5 M. This process is characterized by luminescence, using a pyrene probe, light-scattering measurements, and transmission electron microscopy. The novelty of the reported systems is their ability to self-aggregate into nanometric, rigid, and spherical particles in a controlled way (mean diameter: 10, 60, and ~300 nm), opening large perspectives for various applications. In particular, a record-high relaxivity (r1 = 53 mM-1 s-1 at 20 MHz, T = 25°C) is observed for the aggregates of 1:2 Gd podate, which is not modified upon addition of an equimolar quantity of ZnII.
- Fatin-Rouge, Nicolas,Toth, Eva,Perret, Didier,Backer, Robin H.,Merbach, Andre E.,Buenzli, Jean-Claude G.
-
p. 10810 - 10820
(2007/10/03)
-
- Novel nonprostanoid prostacyclin (PGI2) mimetics with heterocyclic moiety
-
Structural modification of [2-(2-benzhydryloxyiminopentyl)-1,2,3,4-tetrahydro-5-naphthyloxy]acetic acid (4), previously identified as a PGI2 agonist without a PG skeleton, was examined. Conversion of the oxime moiety in 4 to the pyrazole led to [2-(4-benzhydrylpylazoyl)methyl-1,2,3,4-tetrahydro-5-naphthyloxy]acetic acid (34) which strongly inhibited ADP-induced aggregation of human platelets in vitro.
- Nagao, Yuuki,Takahashi, Kanji,Torisu, Kazuhiko,Kondo, Kigen,Hamanaka, Nobuyuki
-
p. 517 - 523
(2007/10/03)
-
- REACTIONS OF TETRAFLUOROETHENE OLIGOMERS. PART XII. CYCLOADDITION REACTIONS OF 3,3,4,4,4-PENTAFLUORO-2-PENTAFLUOROETHYL-2-TRIFLUOROMETHYLDIAZOBUTANE. A NOVEL SYNTHESIS OF PYRAZOLES
-
The title diazoalkane (1) reacts smoothly with a variety of electron deficient alkenes to give, unexpectedly, the corresponding pyrazole derivatives.Thus, reaction with methyl or ethyl propenoate affords the methyl and ethyl esters of pyrazole-3-carboxylic acid (2) and (3).Reaction with diethyl maleate yields 3,4-bis-(ethoxycarbonyl)pyrazole (4), and dimethyl maleate gives the corresponding dimethyl ester (5).Treatment of (1) with propenonitrile afforded 3-cyanopyrazole (6), and with propenoic acid the corresponding pyrazole-3-carboxylic acid (7) was obtained.In all of these reactions two side products were isolated, namely perfluoro-(3-methylpent-2-ene) (8) and 3H-3-trifluoromethyldecafluoropentane (9).A mechanistic rationale for these unusual and potentially useful reactions is given.
- Coe, Paul L.,Cook, Michael I.
-
p. 323 - 330
(2007/10/02)
-