- A Triazolotriazine-Based Dual GSK-3β/CK-1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition
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Glycogen synthase kinase 3β (GSK-3β) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC50(GSK-3β)=0.17 μm; IC50(CK-1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.
- Redenti, Sara,Marcovich, Irene,De Vita, Teresa,Pérez, Concepción,De Zorzi, Rita,Demitri, Nicola,Perez, Daniel I.,Bottegoni, Giovanni,Bisignano, Paola,Bissaro, Maicol,Moro, Stefano,Martinez, Ana,Storici, Paola,Spalluto, Giampiero,Cavalli, Andrea,Federico, Stephanie
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supporting information
p. 310 - 314
(2019/01/24)
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- COMPOUNDS, COMPOSITIONS AND METHODS OF INCREASING CFTR ACTIVITY
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The present disclosure features compounds such as those having the Formulae (I) and (II), which can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells. The present disclosure also features methods of treating a condition associated with decreased CFTR activity or a condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound, such as a compound of Formula (I) or (II).
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Paragraph 0133
(2017/02/24)
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- METHODS OF TREATING PULMONARY DISEASES AND DISORDERS
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The present disclosure features disclosed method of treating disorders such as COPD, bronchitis and/or asthma using disclosed compounds, optionally together with one or more additional active agents. Contemplated methods include administrating orally or by inhalation to a patient one or more disclosed compounds.
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Paragraph 0133
(2017/07/14)
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY
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The present disclosure is directed to disclosed compounds that increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells.
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Paragraph 0158
(2016/07/27)
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- Synthesis and antimicrobial activity of N-aryl-4-(cyano/alkoxycarbonyl)-5-(pyridin-3-yl)-1H/3H-1,2,3-triazole derivatives
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A convenient synthesis of a new series of N-aryl-5-(pyridin-3-yl)-1H/3H-1,2,3-triazole-4-carbonitriles and alkyl N-aryl-5-(pyridin-3-yl)-1H/3H-1,2,3-triazole-4-carboxylic acid esters is reported. The newly synthesized 5-(pyridin-3-yl)-1,2,3-triazole derivatives are evaluated for their antibacterial and antifungal activity. Some of these triazole derivatives have exhibited moderate antimicrobial activity.
- Komsani, Jayaram Reddy,Avula, Sreenivas,Koppireddi, Satish,Koochana, Pranay Kumar,Usn, Murty,Yadla, Rambabu
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p. 764 - 772
(2015/05/13)
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- Demonic axe-like conjugated alkynes in combating microbes
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A new series of disubstituted alkynes was obtained by microwave induced internal splitting of the corresponding β-oxo- alkylidenetriphenylphosphoranes. The antimicrobial potential of these conjugated alkynes and phosphoranes was assayed in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Staphylococcus epidermidis), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and five fungal strains (Aspergillus niger, Candida albicans, Aspergillus flavus, Candida rugosa, Saccharomyces cerevisiae). The 3-pyridylalkyne derivatives viz., 3-(6-chloropyridin-3-yl)propynenitrile (6a), 3-(2-chloropyridin-3-yl)propynenitrile (6b), ethyl 3-(6-chloropyridin-3-yl) propiolate (6c), iso-propyl 3-(6-chloropyridin-3-yl)propiolate (6d) and 3-(2,6-dichloro-5-fluoropyridin-3-yl)propynenitrile (6e) were found to be highly potent towards all tested microorganisms except E. coli.
- Komsani, Jayaram Reddy,Koppireddi, Satish,Avula, Sreenivas,Koochana, Pranay Kumar,Yadla, Rambabu
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p. 132 - 138
(2013/10/01)
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- A modular synthesis of teraryl-based α-helix mimetics, part 1: Synthesis of core fragments with two electronically differentiated leaving groups
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Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics. Central to our strategy is the use of a benzene core unit featuring two leaving groups of differentiated reactivity in the Pd-catalyzed cross-coupling used for terphenyl assembly. With the halogen/diazonium route and the halogen/triflate route, two strategies have successfully been established. The synthesis of core building blocks with aliphatic (Ala, Val, Leu, Ile), aromatic (Phe), polar (Cys, Lys), hydrophilic (Ser, Gln), and acidic (Glu) amino acid side chains are reported. Turn on: Teraryl-based α-helix mimetics can be effectively produced by sequential Suzuki coupling of a central core fragment featuring electronically differentiated leaving groups with aryl boronic pinacol esters (see scheme; dppf=1,1′-bis(diphenylphosphino) ferrocene, DME=dimethoxyethane, Pin=pinacol, Tf=trifluoromethanesulfonyl). With a set of only 2×18 building blocks, all permutations of α-helix mimetics can be produced. Copyright
- Peters, Martin,Trobe, Melanie,Tan, Hao,Kleineweischede, Rolf,Breinbauer, Rolf
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supporting information
p. 2442 - 2449
(2013/04/24)
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- Synthesis, thermal reactivity, and kinetics of stabilized phosphorus ylides, part 2: [(Arylcarbamoyl) (cyano)-methylene] triphenylphos-phoranes and their thiocarbamoyl analogues
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A series of five cyano(arylcarbamoyl) phosphorus ylides 2 and five cyano-(arylthiocarbamoyl) phosphorus ylides 3 are prepared and fully characterized. Pyrolytic reaction products of a representative example of each type obtained by flash vacuum pyrolysis technique show that they undergo thermal extrusion of Ph3PO or Ph3PS. Kinetic study of the gas-phase pyrolysis of each ylide by static method shows that these reactions are unimolecular and first order with no significant substituent effect, but the thiocarbamoyl ylides 3 react 40-65 times more rapidly than their carbamoyl analogues 2.
- Aitken, R. Alan,Al-Awadi, Nouria A.,El-Dusouqui, Osman M.E.,Farrell, Dorcas M.M.,Kumar, Ajith
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p. 496 - 502
(2008/02/09)
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- Aza-Wittig reaction of fluoroalkylated N-vinylic phosphazenes with carbonyl compounds. Usefulness of 2-azadienes for the preparation of fluoroalkyl pyridine derivatives
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A method for the preparation of 3-fluoroalkyl substituted 2-aza-butadienes 6 by aza-Wittig reaction of 3-fluoroalkyl-N-vinylic phosphazenes 4 and aldehydes 5 is reported. [4+2] Cycloaddition reaction of these heterodienes 6 with enamines 9 gives fluoroalkyl substituted pyridine 15, 16, 24-27 and isoquinoline 12-14, 20 derivatives.
- Palacios, Francisco,Alonso, Concepción,Rubiales, Gloria,Villegas, Maite
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p. 2779 - 2794
(2007/10/03)
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- Synthesis of chlorophyll-a homologs by Wittig and Knoevenagel reactions with methyl pyropheophorbide-d
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The formyl group at the 3-position of methyl pyropheophorbide-d reacted with phosphorous ylides and activated methylene compounds to give efficiently the corresponding 3-(2-substituted ethenyl)chlorins compounds as a product of Wittig and Knoevenagel reactions. The trans-isomers of the synthetic chlorins, methyl 32-substituted pyropheophorbide-a had visible bands absorbing longer wavelengths than the cis-isomers and the 32-unsubstituted chlorin, methyl pyropheophorbide-a. 32,32-Disubstitution strongly affected the absorption bands compared with the bands of the 32-monosubstituted chlorins. The absorption, fluorescence and circular dichroism spectra were dependent upon the 3-substituents conjugated with the chlorin chromophore.
- Tamiaki, Hitoshi,Kouraba, Mitsuru
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p. 10677 - 10688
(2007/10/03)
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- REGIOSELECTIVE REPLACEMENT OF THE HYDROXY GROUP IN ALCOHOLS BY MEANS OF TRIHALOACETIC DERIVATIVES IN PRESENCE OF TRIPHENYLPHOSPHINE
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The investigation of the reactions of trichloroacetonitrile with 2-decanol, 2-methyl-3-octanol, 2,4-dimethyl-3-pentanol, and 2,2-dimethyl-1-propanol in presence of triphenylphosphine shows that the formation of alkyl chlorides from the corresponding alcohols goes regiospecifically: Even for 2,4-dimethyl-3-pentanol the amount of the isomeric chloride does not exceed 1percent, while neopentyl alcohol is converted into neopentyl chloride in 95percent yield.On the introduction of "external" nucleophiles (iodide and thiocyanate ions) into the reaction mixture the predominating reaction product is the alkyl chloride.As a result of the reaction of bromotrichloromethane with 1-nonanol and triphenylphosphine a mixture of the alkyl chloride and the alkyl bromide is formed.
- Matveeva, E. D.,Yalovskaya, A. I.,Cherepanov, I. A.,Bundel', Yu. G.,Kurts, A. L.
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p. 1409 - 1415
(2007/10/02)
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- Design of Inhibitors from the Three-Dimensional Structure of Alcohol Dehydrogenase. Chemical Synthesis and Enzymatic Properties
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Inhibitors of liver alcohol dehydrogenase were designed from the three-dimensional structure of the enzyme.The ligand to the catalytic zinc ion is an amide group or, better, a formamide group.With the latter function, a hydrogen bond between the NH group and the hydroxyl group of Ser-48 may be formed.The hydrophobic substrate binding site brings structural restraints. α-ω bifunctional molecules show good inhibitory properties possibly due to the interactions with polar residues at the entrance of the substrate binding site.
- Freudenreich, Charles,Samama, Jean-Pierre,Biellmann, Jean-Francois
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p. 3344 - 3353
(2007/10/02)
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- Synthesis of Conjugated Alkynenitriles
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The synthesis of 2-butynenitrile (7a), 3-(4-methoxyphenyl)-(7b)-, 3-(4-ethoxyphenyl)-(7c)-, 3-(4-nitrophenyl)-(7d)- and 3-(3,4,5-trimethoxyphenyl)-(7e)-propynenitriles by thermal decomposition of the corresponding acylcyanomethylenetriphenylphosphoranes (6a-e) is described.The ethoxycarbonylcyanomethylenetriphenylphosphorane (6f) under the same conditions does not give the alkynenitrile.Cleavage to triphenylphosphine oxide and acetylenic nitrile is the predominant fragmentation observed in the mass spectra of all the ylids.
- Yalda, R,Rao, V. Subrahmanyeswara,Rao, Jampani Madhusundana
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p. 1046 - 1048
(2007/10/02)
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- SYNTHESIS OF PERFLUORO-2-ALKYNENITRILES
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Intramolecular Wittig reaction has been applied to the synthesis of perfluoro-2-alkynenitriles (4a, b, c).
- Huang, Y. Z.,Shen, Yanchang,Ding, Weiyu,Zheng, Jianhua
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p. 5283 - 5284
(2007/10/02)
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- Ring Contraction of 2-Azidoquinoline and Quinoxaline 1-Oxides
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Thermal ring contraction of 2-azidoquinoline 1-oxide with loss of nitrogen did not lead to the desired 2-cyano-1-hydroxyindole.Instead, 2-cyanoisatogen (9), 2,2'-dicyano-3,3'-bis (10), and 2-aminoquinoline 1-oxide (7) were formed.The mechanism is believed to involve an intermolecular addition to the intermediate cis-o-nitrosocinnamonitrile formed in a concerted ring-opening nitrogen loss, i.e., not involving a nitrene intermediate.In accord with this, both 2-azido-4-methylquinoline 1-oxide and 2-azidoquinoxaline 1-oxide give the expected 2-cyano-1-hydroxy-3-methylindole (18) and 2-cyano-1-hydroxybenzimidazole (26), respectively.
- Abramovitch, Rudolph A.,Cue, Berkeley W.
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p. 5316 - 5319
(2007/10/02)
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