- Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition
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Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma.
- Balasubramaniam, Sivaraman,Vijayan, Sajith,Goldman, Liam V.,May, Xavier A.,Dodson, Kyra,Adhikari, Sweta,Rivas, Fatima,Watkins, Davita L.,Stoddard, Shana V.
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Read Online
- Heterobimetallic metallacrown of EuIIICuII5 with 5-methyl-2-pyrazinehydroxamic acid: Synthesis, crystal structure, magnetism, and the influence of CuII ions on the photoluminescent properties
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A 3d-4f heterobimetallic metallacrown with the formula of [EuCu5(5mpzHA)5(NO3)3/2(H2O)6]2·3NO3·4H2O·5CH3OH (MC1) has been prepared using the stirring method from a mixture of 5-methyl-2-pyrazinehydroxamic acid (5mpzHA), Cu(AcO)2·H2O, and Eu(NO3)3·5H2O salts in methanol under reflux, which yielded single crystals after slow solvent evaporation. Single crystal X-ray diffraction analysis shows a crown-like [EuCu5(5mpzHA)5] core with the 15-MC-5 system, with five CuII and one EuIII ions occupying the rim and the dome of the crown, respectively. Water molecules oxygen atoms and one nitrate anion fill the coordination sphere around the EuIII ion, which exhibits a MFF-9 shape. The MC1 is made up of two [EuCu5(5mpzHA)5(NO3)3/2(H2O)6] metallacrown units connected by one coordinated nitrate ion, where intramolecular hydrogen bonding interactions generate aR86(18) supramolecular macrocycle leading a two-dimensional supramolecular network. The emission and excitation spectra of MC1 show the absence of EuIII emission and f-f transitions, probably due to the paramagnetic nature of the CuII ions which play a key role in quenching the fluorescence in MC1. The observed magnetic properties are attributed to antiferromagnetic interactions among the CuII ions within the metallacrown rim plus the depopulation of EuIII excited Stark sublevels. This magnetic behavior was also supported by the EPR spectroscopy which presents a superposition of signals of the termally populated state 7F1 of EuIII and CuII ions at room temperature and a sole signal of CuII ion at 4 K.
- Paiva, Fábio F.,Ferreira, Leonildo A.,Rosa, Iara M.L.,da Silva, Rafaela M.R.,Sigoli, Fernando,Cambraia Alves, Odivaldo,Garcia, Flávio,Guedes, Guilherme P.,Marinho, Maria Vanda
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- ISOXAZOLIDINES AS RIPK1 INHIBITORS AND USE THEREOF
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The present invention relates to isoxazolidines of formula I and their use as receptor-interacting protein kinase 1 inhibitors, for example in the treatment of diseases and disorders mediated by RIP kinase (1) such as rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.
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(2021/12/31)
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- Synthesis and Characterization of 2-(2-Pyridinyl)pyrazine and 2,2′-Bipyrazine Derivatives
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A convenient and high yield preparation of derivatives of 2-(2-pyridinyl)pyrazine and derivatives of 2,2′-bipyrazine compounds from their derivatives of bromopyrazine using Stille coupling is reported. X-ray structures, elemental analyses, 1H, 13C-NMR, and mass spectral data of the compounds are given.
- KomReddy, Venugopal,Rillema, D. Paul,Nguyen, Huy,Kadel, Lava
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p. 972 - 979
(2019/02/05)
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- PROCESS FOR PREPARATION OF GLIPIZIDE
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The present invention discloses a simple, economic, consistent, commercially viable and industrially applicable process for preparation of Glipizide in high yield and highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
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Page/Page column 19
(2018/05/24)
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- Discovering a new class of antifungal agents that selectively inhibits microbial carbonic anhydrases
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Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones. The mechanism of action of these inhibitors was investigated against an important fungal pathogen, Cryptococcus neoformans, revealing that they are also able to inhibit CA in microbial cells growing in vitro. At our best knowledge, this is the first report on newly designed synthetic compounds selectively targeting β-CAs and provides a proof of concept of microbial CAs suitability as an antimicrobial drug target.
- Annunziato, Giannamaria,Giovati, Laura,Angeli, Andrea,Pavone, Marialaura,Del Prete, Sonia,Pieroni, Marco,Capasso, Clemente,Bruno, Agostino,Conti, Stefania,Magliani, Walter,Supuran, Claudiu T.,Costantino, Gabriele
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p. 1537 - 1544
(2018/10/15)
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- Pyrazine biosynthesis in corynebacterium glutamicum
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The volatile compounds released by Corynebacterium glutamicum were collected by use of the CLSA technique (closed-loop stripping apparatus) and analysed by GC-MS. The headspace extracts contained several acyloins and pyrazines that were identified by their synthesis or comparison to commercial standards. Feeding experiments with [2H7]acetoin resulted in the incorporation of labelling into trimethylpyrazine and tetramethylpyrazine. Several deletion mutants targeting genes of the primary metabolism, were constructed to elucidate the biosynthetic pathway to pyrazines in detail. A deletion mutant of the ketol-acid reductoisomerase was not able to convert the acetoin precursor (S)2-acetolactate into the pathway intermediate (R)-2,3-dihydroxy-3-methylbutanoate to the branched amino acids. This mutant requires valine, leucine, and isoleucine for growth and produces significantly higher amounts and more different compounds of the acyloin and pyrazine classes. Gene deletion of the acetolactate synthase (AS) resulted in a mutant that is not able to convert pyruvate into (5)-2-acetolactate. This mutant also requires branched amino acids and produces only very small amounts of pyrazines likely from valine via the valine biosynthetic pathway operating in reverse order. A ΔASΔKR double mutant was constructed that does not produce any pyrazines at all. These results open up a detailed biosynthetic model for the formation of alkylated pyrazines via acyloins.
- Dickschat, Jeroen S.,Wickel, Susanne,Bolten, Christoph J.,Nawrath, Thorben,Schulz, Stefan,Wittmann, Christoph
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supporting information; experimental part
p. 2687 - 2695
(2010/08/07)
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- The methyl group as a source of structural diversity in heterocyclic chemistry: Side chain functionalization of picolines and related heterocycles
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(Chemical Equation Presented) The reaction of 2-picoline at the methyl group with NDA and KDA followed by dimethyldisulfide trapping furnished, respectively, dithioacetals and trithioortho esters with high selectivity. The method was successfully applied to other methyl-substituted pyridines, quinolines, and pyrazines. Dithioketals were prepared by a one-pot procedure involving the reaction of metalated 2-picoline with 2 equiv of dimethyldisulfide followed by in situ trapping with a second electrophile. All of the generated thio-substituted compounds were efficiently transformed in presence of mercury salts or under oxidizing conditions to other functional groups comprising aldehydes, ketones, ketals, thiol esters, orthoesters, and esters.
- Mamane, Victor,Aubert, Emmanuel,Fort, Yves
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p. 7294 - 7300
(2008/02/11)
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- Method for the preparation of 5-methylpyrazine-2-carboxylic acid-4-oxide and its salts
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Methods for the preparation of pharmaceutically acceptable salts of 5-methylpyrazine-carboxylic acid-4-oxide by using the oxidizing agent OXONE? for the N-oxidation of C1-4 methylpyrazinecarboxylic acid esters. The pharmaceutically acceptable salts are then formed by the saponification of the esters followed by alcohol precipitation.
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Page/Page column 2
(2008/06/13)
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- Pharmaceutically acceptable inorganic and organic salts of 5-methylpyrazine-2-carboxylic acid-4-oxide
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Methods for the preparation of pharmaceutically acceptable organic or inorganic salts of 5-methylpyrazinecarboxylic acid-4-oxide esters including tris(hydroxymethyl)aminomethanol, N,N-dimethylethanolamine, N-methyl-D-glucamine, L-Lysine, L-arginine, Na, K, Ca and Mg. The esters of 5-methylpyrazinecarboxylic acid-4-oxide are oxidized in aqueous hydrogen peroxide at a pH of 2.5 to 7 in the presence of a catalyst selected from the group consisting of sodium tungstate, tungstic acid and ammonium heptamolybdate. The salts are formed by saponification of the esters followed by alcohol precipitation, or by reaction with a metal trimethylsilanoate, or by the reaction of organic bases with the saponified acids.
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(2010/02/14)
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- CXCR4-ANTAGONISTIC DRUGS COMPRISING NITROGEN-CONTAINING COMPOUND
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To provide novel nitrogen-containing compounds having antagonism to CXCR4 and remedies for disease, such as rheumatism, cancer metastasis, etc., based on the CXCR4 antagonism. Nitrogen-containing compounds represented by the following general formula and
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(2010/02/05)
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- NITROGENOUS COMPOUNDS AND ANTIVIRAL DRUGS CONTAINING THE SAME
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The present invention provides novel compounds having antiviral activities and antiviral drugs containing the compounds as the active ingredient. The compounds are shown by the following general formula (1), wherein typically A1 and A2 are each guanidine or a group of the general fomula (ia) ; A3 is a mono- or poly-cyclic heteroaromatic ring contining 1 or 2 heteroatoms ; B1 is a single bond or alkylene group; R1 is hydrogen or alkyl group; W is an alkylene having 2-3 carbons, a cycloalkylene having 5-10 carbons, aromatic ring having 6-10 carbons, or a heteroaromatic ring having 5-10 carbons; y is C(=O)-; x is -C(=O)-NH-; n1 is an integer of 1-2; n2 is an integer of 2-3; D is a substituent selected from among various groups.
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- Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151)
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Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of
- Macdonald, Simon J. F.,Dowle, Michael D.,Harrison, Lee A.,Clarke, Geoffrey D. E.,Inglis, Graham G. A.,Johnson, Martin R.,Shah, Pritom,Smith, Robin A.,Amour, Augustin,Fleetwood, Gill,Humphreys, Davina C.,Molloy, Christopher R.,Dixon, Mary,Godward, Rosalind E.,Wonacott, Alan J.,Singh, Onkar M. P.,Hodgson, Simon T.,Hardy, George W.
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p. 3878 - 3890
(2007/10/03)
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- Pyrazinoic Acid Esters with Broad Spectrum in Vitro Antimycobacterial Activity
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A series of substituted pyrazinoic acid esters has been prepared and examined for their in vitro activity against Mycobacterium avium and Mycobacterium kansasii as well as mycobacterium tuberculosis.Modification of both the pyrazine nucleus and the ester functionality have been very successfull in expanding the activity of pyrazinamide to include M. avium and M. kansasii, organisms normally not susceptible to pyrazinamide.Several of these compounds have activities 100-1000-fold greater than that of pyrazinamide against M. tuberculosis.
- Cynamon, Michael H.,Gimi, Rayomand,Gyenes, Ferenc,Sharpe, Cindy A.,Bergmann, Kathryn E.,et al.
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p. 3902 - 3907
(2007/10/02)
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