- Metallation of 2(1H)-quinolinone: Synthesis of 3-substituted compounds
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The ortho-directing effect of the amide function in the regioselective lithiation of 2(1H)-quinolinone has been confirmed. Direct or indirect electrophilic substitution may compete with previous multistep procedures to obtain 3-substituted compounds.
- Fernandez,De La Cuesta,Avendano
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- Synthesis and in vivo evaluation of N-ethylamino-2-oxo-1,2-dihydro- quinoline-3-carboxamide for inhibition of intestinal tumorigenesis in APC Min/+ mice
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A selective KGFR tyrosine kinase inhibitor, N-ethylamino-2-oxo-1,2-dihydro- quinoline-3-carboxamide, was synthesized and its possible inhibitory effects on the development of colon polyps and colorectal tumors was examined in APC Min/+ mice, a mouse model of human intestinal familial adenomatous polyposis. The present study shows for the first time that a dietary administration of a selective KGFR tyrosine kinase inhibitor lacks the overt-toxicities and significantly reduced the growth of small intestinal polyps in both male and female APCMin/+ mice. This inhibition of polyp growth appears to occur at a greater extent in female mice.
- Pathuri, Gopal,Li, Qian,Mohammed, Altaf,Gali, Hariprasad,Pento, J. Thomas,Rao, Chinthalapally V.
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Read Online
- Antifungal activity, mode of action variability, and subcellular distribution of coumarin-based antifungal azoles
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Azole antifungals inhibit the biosynthesis of ergosterol, the fungal equivalent of cholesterol in mammalian cells. Here we report an investigation of the activity of coumarin-substituted azole antifungals. Screening against a panel of Candida pathogens, including a mutant lacking CYP51, the target of antifungal azoles, revealed that this enzyme is inhibited by triazole-based antifungals, whereas imidazole-based derivatives have more than one mode of action. The imidazole-bearing antifungals more effectively reduced trailing growth associated with persistence and/or recurrence of fungal infections than triazole-based derivatives. The imidazole derivatives were more toxic to mammalian cells and more potently inhibited the activity of CYP3A4, which is one of the main causes of azole toxicity. Using live cell imaging, we showed that regardless of the type of azole ring fluorescent 7-diethylaminocoumarin-based azoles localized to the endoplasmic reticulum, the organelle that harbors CYP51. This study suggests that the coumarin is a promising scaffold for development of novel azole-based antifungals that effectively localize to the fungal cell endoplasmic reticulum.
- Elias, Rebecca,Benhamou, Raphael I.,Jaber, Qais Z.,Dorot, Orly,Zada, Sivan Louzoun,Oved,Pichinuk, Edward,Fridman
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p. 779 - 790
(2019/07/10)
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- FLUORESCENT DYE AGENT AND CARBOSTYRIL COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel fluorescent dye agent. SOLUTION: A fluorescent dye agent contains a carbostyril compound represented by formula (1) [in the formula (1), R1 is H, a halogen atom, a hydroxyl group, a cyano group, a nitro group or the like; R2 is O; R3 is a halogen atom, a carboxyl group, an ester group, an amide group or the like; R4-R6 and R8 independently represent H, a halogen atom, a nitro group, a cyano group or the like, where mutually adjacent groups of R4-R8 may be bound to form a ring; R7 is H, a substituted or unsubstituted aliphatic group or the like]. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0126; 0127; 0128
(2019/04/03)
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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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- Structure-activity relationships studies of the anti-angiogenic activities of linomide
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The synthesis and anti-angiogenic activities of linomide and its analogues are reported. Three of the analogues are 3.3-69 times more potent than linomide at inhibiting blood vessel formation in the CAM angiogenesis assay. These compounds possessed consid
- Shi, Jiandong,Xiao, Zili,Ihnat, Michael A.,Kamat, Chandrashekhar,Pandit, Bulbul,Hu, Zhigen,Li, Pui-Kai
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p. 1187 - 1189
(2007/10/03)
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- Synthesis of some novel quinoline-3-carboxylic acids and pyrimidoquinoline derivatives as potential antimicrobial agents
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The synthesis and in vitro antimicrobial evaluation of several quinoline and pyrimidoquinoline derivatives are described. Treatment of 7-substituted quinolin-2(1H)-one-3-carboxylic acids 2 a-c with phosphoryl chloride or thionyl chloride gave rise to the 7-substituted 2-chloroquinoline-3-carboxylic acids 3 a-c and 7-substituted 2-chloro-3-chlorocarbonylquinolines 5 a-c respectively. The 2-chloro function in compounds 3 a-c was replaced by 2-aminothiazole or 2-aminopyridine to give 2-(thiazol-2-yl)aminoquinoline-3-carboxylic acids 4 a-c or 2-(pyrid-2-yl)aminoquinoline-3-carboxylic acids 4 d-f. Treatment of 5 a-c with the same heterocyclic amines at room temperature furnished the corresponding 7-substituted 2-chloro-3-heteryl- aminocarbonylquinolines 6a-f. The tetracyclic 9-substituted thiazolo[3′,2′: 1,2]-pyrimido[4,5-b]quinolin-5-ones 7a-c and 10-substituted pyrido[1′,2′: 1,2]- pyrimido[4,5-b]quinolin-6-ones 7 d-f were synthesized by heating 5 a-c with the heterocyclic amines in toluene or by heating 6 a-f under reflux in dimethylformamide. The products were evaluated in vitro for potential antimicrobial activity.
- El-Sayed, Ola A.,Al-Bassam, Badr A.,Hussein, Maher E.
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p. 403 - 410
(2007/10/03)
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- Solid phase synthesis of substituted quinolin-2(1H)-one-3-carboxylic acids via an intramolecular knoevenagel condensation
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A solid phase synthesis of substituted quinolin-2(1H)-one-3-carboxylic acids is described. The products are formed in a two-step synthesis in which ortho-aminophenones are first coupled to malonic acid bound to the Wang Resin followed by ring closure via an intramolecular Knoevenagel condensation.
- Watson, Brett T.,Christiansen, Gerda E.
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p. 9839 - 9840
(2007/10/03)
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- Synthesis of dibenzonaphthyridin-6(5H-)ones
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Substituted dibenzonaphthyridin-6(5H)-ones (5a-g) have been synthesized by treating various 2-oxoquinoline--3-carboxanilides (4a-g) with polyphosphoric acid.The precursors have been readily obtained by the condensation of 2-quinoline-3-carboxyli
- Vijayalakshmi, S.,Rajendran, S. P.
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p. 159 - 162
(2007/10/02)
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- Base-catalyzed electrophilic substitution in 2(1H)-quinolinones
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Instead of tandem conjugate addition-α-alkylation to C3=C4 double bond of 2(1H)-quinolinones, regioselective C3-lithiation and subsequent C3-alkylation takes place by reaction with two equivalents of n-butyllithium and several electrophiles.
- Gonzales, Rosario,Ramos, M. Teresa,Cuesta, Elena de la,Avendano, Carmen
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p. 315 - 322
(2007/10/02)
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- Process for the preparation of 2-hydroxypyridine or quinoline compounds
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The present invention relates to a process for the preparation of hydroxypyridine based compounds. The process comprises the step of: in water, reacting a pyridine based compound with the proviso that the second position on the nitrogen ring is unsubstituted and the fourth position in the nitrogen ring is not substituted with halogen, with elemental fluorine at a temperature of about -25° to about +30° C. for a time sufficient to form a 2-hydroxypyridine based compound. The resulting 2-hydroxypyridine or quinoline carboxylic acids and esters are useful as herbicide and pharmaceutical intermediates.
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- Directed ortho-Lithiation of Chloroquinolines. Application to Synthesis of 2,3-Disubstituted Quinolines
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2-, 3- and 4-Chloroguinolines were selectively lithiated at low temperature by lithium diisopropylamide at the more acidic C-3, C-4 and C-3 positions respectively.Reaction of 2-chloro-3-lithioquinoline with electrophiles led to various 2,3-disubstituted quinolines.The versatility of this functionalization methodology is enhanced by the C-2 halogen reactivity towards oxygen or nitrogen nucleophiles.So, a great variety of 2,3-disubstituted quinolines were synthesized, such as 2-chloro, 2-alkoxy, 2-aminoquinolines or 2-quinolones bearing an hydroxy, carbonyl (aldehyde, ketone or carboxylic acid), iodo, trimethylsilyl or boronic acid moiety at the C-3.Some of the resulting 2,3-disubstituted synthons were annelated to tetracyclic polyaromatics, which possess the xanthone or indole structure.This could be achieved via further functionalization of the quinoline ring either by SNAr2 or heteroaromatic cross-coupling reactions, after the first directed-lithiation step.
- Marsais, F.,Godard, A.,Queguiner, G.
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p. 1589 - 1594
(2007/10/02)
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- Carbostyril derivatives
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Disclosed are carbostyril derivatives and their salts of the formulas STR1 The compounds have anti-peptic ulcer effects, and are useful as a treating agent for curing peptic ulcers in the digestive system, such as ulcers in the stomach and in the duodenum. The compounds particularly have prophylaxis and curing effects for treating chronic ulcers, for example experimental acetic acid-induced ulcers and cautery ulcers, with both low toxicity and few side-effects. Also disclosed are processes for preparing the compounds and for preparing pharmaceutical compositions containing them.
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- OXIDATION OF METHYLQUINOLINES WITH NICKEL PEROXIDE
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Room temperature oxidation of 2-(or 3-)methylquinoline-3-(or 2-)carboxylic acid with 3.25 eq nickel peroxide in aqueous base gives quinoline-2,3-dicarboxylic acid in high yield.No reaction occurs for methylpyridinecarboxylic acids under these conditions.
- Ladner, David W.
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p. 157 - 162
(2007/10/02)
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- Novel Reactions of Carbon Suboxide. VI. Synthesis of 2-Oxo-1-benzopyran- and 2-Oxoquinoline-3-carboxylic Acid Hydrazides
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A simple, one step synthesis of 2-oxo-1-benzopyran- and 2-oxoquinoline-3-carboxylic acid hydrazides from carbon suboxide and hydrazones is described.
- Bonsignore, Leonardo,Cabiddu, Salvatore,Loy, Giuseppe,Secci, Mario
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p. 463 - 464
(2007/10/02)
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