- Chemical probes to study ADP-ribosylation: Synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3
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The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl] propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of 55 compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.
- Lindgren, Anders E.G.,Karlberg, Tobias,Ekblad, Torun,Spjut, Sara,Thorsell, Ann-Gerd,Andersson, C. David,Nhan, Ton Tong,Hellsten, Victor,Weigelt, Johan,Linusson, Anna,Schüler, Herwig,Elofsson, Mikael
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p. 9556 - 9568
(2014/01/06)
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- AZO PIGMENT, PIGMENT DISPERSION CONTAINING THE AZO PIGMENT, AND COLORING COMPOSITION
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Provided is an azo pigment having excellent coloring characteristics such as high tinctorial strength and hue and having excellent durability such as high resistance to light and ozone, a pigment dispersion containing the azo pigment, and a coloring composition. An azo pigment represented by the following general formula (1), a tautomer of the azo pigment, and a salt or a hydrate thereof: (In the general formula (1), G0 and G1 each independently represents a non-metal atomic group which can form a 5- or 6-membered heterocyclic ring wherein each heterocyclic ring may be unsubstituted or may have a substituent; each heterocyclic ring may be a monocyclic ring or a condensed ring; X represents a hetero atom; n represents an integer of 1 to 4; when n = 2, the compound of formula (1) represents a dimer formed via A or a heterocyclic group represented by G0 or G1;. when n = 3, the compound of formula (1) represents a trimer formed via A and/or a heterocyclic group represented by G0 or C1; when n = 4, the compound of formula (1) represents a tetramer formed via A and/or a heterocyclic group represented by G0 or G1; A represents any one selected from the group of the specific substituents.)
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Page/Page column 173-174
(2011/01/11)
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- Identification of novel quinazolin-4(3H)-ones as inhibitors of thermolysin, the prototype of the M4 family of proteinases
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A combinatorial series of novel quinazolin-4(3H)-ones were synthesised and their structures were established based on spectroscopic data (IR, NMR, EI-MS, and FAB-MS). The compounds were tested for inhibition of the zinc metalloproteinase thermolysin (TLN) utilizing a chemical array-based approach. Some of the compounds were found to inhibit TLN, with IC50 values ranging from 0.0115 μM (compound 3) to 122,637 μM (compound 29). Compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3H)-one] (IC50 = 0.0115 μM) and compound 35 [3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4 (1H)-one] (IC50 = 0.2477 μM) were found to be the most potent inhibitors.
- Khan, Mahmud Tareq Hassan,Khan, Rasool,Wuxiuer, Yimingjiang,Arfan, Mohammad,Ahmed, Manzoor,Sylte, Ingebrigt
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experimental part
p. 4317 - 4327
(2010/09/12)
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- 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase
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Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
- Tedesco, Rosanna,Shaw, Antony N.,Bambal, Ramesh,Chai, Deping,Concha, Nestor O.,Darcy, Michael G.,Dhanak, Dashyant,Fitch, Duke M.,Gates, Adam,Gerhardt, Warren G.,Halegoua, Dina L.,Han, Chao,Hofmann, Glenn A.,Johnston, Victor K.,Kaura, Arun C.,Liu, Nannan,Keenan, Richard M.,Lin-Goerke, Juili,Sarisky, Robert T.,Wiggall, Kenneth J.,Zimmerman, Michael N.,Duffy, Kevin J.
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p. 971 - 983
(2007/10/03)
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- Reaction of Nitriles under Acidic Conditions. Part I. A General Method of Synthesis of Condensed Pyrimidines
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Nitriles are known to give rise to salts of different compositions with halogen acids.Many of the reactions undergone by nitriles under the influence of halogen acids are, in many cases, assumed to proceed via the intermediate formation of highly reactive
- Dave, K. G.,Shishoo, G. J.,Devani, M. B.,Kalyanaraman, R.,Ananthan, S.,et. al.
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p. 1497 - 1500
(2007/10/02)
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