- Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators
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Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure-activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, 57 (TUG-1907) and 63 (TUG-2015), showed improved solubility and preserved potency. Of these, 57, with EC50 = 145 nM and a solubility of 33 μM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, 63, with EC50 = 162 nM and a solubility of 9 μM, showed lower clearance and seems better suited for in vivo studies. Using 57, we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.
- Ulven, Elisabeth Rexen,Quon, Tezz,Sergeev, Eugenia,Barki, Natasja,Brvar, Matjaz,Hudson, Brian D.,Dutta, Palash,Hansen, Anders H?jgaard,Bielefeldt, Line O.,Tobin, Andrew B.,McKenzie, Christine J.,Milligan, Graeme,Ulven, Trond
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p. 3577 - 3595
(2020/04/30)
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- Effective microwave synthesis of bioactive thieno[2,3-d]pyrimidines
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A series of novel 2-Amino-3-cyanothiophenes (2a-2j) were synthesized using heterogeneous base (K2CO3) supported Gewald reaction. Cyclization of 2a-j with formamide and urea in conventional heating as well as microwave irradiation gave thieno[2,3-d]pyrimidines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-ones(4a-4j) respectively. The reaction rates were faster and yields were higher in the microwave conditions. The structures of the compounds were confirmed with elemental analysis, mass spectral analysis, FTIR, 1H NMR and 13C NMR techniques. All the synthesized compounds were subjected to antimicrobial activity (MIC) in vitro by broth dilution method and exhibited a moderate antimicrobial activity.
- Khatri, Taslimahemad T.,Shah, Viresh H.
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p. 3354 - 3358
(2017/05/22)
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- COMPOUNDS ACTIVE TOWARDS BROMODOMAINS
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Disclosed are compounds towards bromodomains, pharmaceutical compositions containing the compounds and use of the compounds in therapy.
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Page/Page column 219
(2016/05/02)
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- Acetyl aceotphenone amine preparation method of the compound
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The invention provides a preparation method of an acetoacetanilide compound. The method comprises the steps of performing diacetylation reaction on aniline compounds and diketene in an organic solvent under anaerobic conditions to obtain the acetoacetanilide compound. The acetoacetanilide compound is prepared under the anaerobic conditions; the acetoacetanilide compound prepared by using the method has a relatively high melting point, thereby being beneficial for applications of the acetoacetanilide compound. In addition, the acetoacetanilide compound prepared by using the method provided by the invention is not easy to agglomerate, and the preparation method of the acetoacetanilide compound, provided by the invention, is relatively low in energy consumption. Experimental results show that the melting point of the acetoacetanilide compound prepared by using the method provided by the invention is 82.5-103 DEG C.
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Paragraph 0043; 0044; 0046
(2017/02/24)
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- NOVEL COMPOUND WITH ANTIBACTERIAL ACTIVITY
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A compound represented by the general formula (I) or a salt thereof having a potent antibacterial activity against bacteria that have acquired resistance to quinolones, and a medicament for prophylactic and/or therapeutic treatment of an infectious disease containing the compound or a salt thereof as an active ingredient, as well as a medicament for prophylactic and/or therapeutic treatment of an infectious disease containing a combination of the compound or a salt thereof, and a quinolone.
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Paragraph 0083-0084
(2016/04/26)
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- An efficient green protocol for the preparation of acetoacetamides and application of the methodology to a one-pot synthesis of Biginelli dihydropyrimidines. Expansion of dihydropyrimidine topological chemical space
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The present study describes the preparation of N-aryl-(15) and N-alkyl-(17) acetoacetamides, in good to excellent yields, using both conventional and microwave heating, by reaction of amine derivatives (14 and 16) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TMD, 12) in aqueous medium. The acetoacetamides were used to prepare novel Biginelli dihydropyrimidine derivatives. The introduction of the amino acid derivatives potentially allows for the exploration of new structural complexity and topologically diversifies the chemical space occupied by this versatile chemical scaffold.
- Gama, Fernando H. S.,De Souza, Rodrigo O. M. A.,Garden, Simon J.
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p. 70915 - 70928
(2015/09/08)
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- Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening
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Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor. Structure-activity relationship (SAR) analysis was performed on analogs of DC-S100 and according to the putative binding mode of DC-S100, structure modifications were made to improve its activity. Of note, compounds DC-S238 and DC-S239, with IC50 values of 4.88 and 4.59 μM, respectively, displayed selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238 and DC-S239 can serve as leads for further investigation as SET7 inhibitors and the chemical toolkits for functional biology studies of SET7.
- Meng, Fanwang,Cheng, Sufang,Ding, Hong,Liu, Shien,Liu, Yan,Zhu, Kongkai,Chen, Shijie,Lu, Junyan,Xie, Yiqian,Li, Linjuan,Liu, Rongfeng,Shi, Zhe,Zhou, Yu,Liu, Yu-Chih,Zheng, Mingyue,Jiang, Hualiang,Lu, Wencong,Liu, Hong,Luo, Cheng
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p. 8166 - 8181
(2015/11/09)
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- Diaryl-substituted polyethers with acetoacet-anilide fragment in the synthesis of dihydro-pyrimidine-containing podands
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The interaction of ortho-aminoaryl polyethers, derivatives of mono-, di-, and triethylene glycol, with acetyl ketene, generated from 2,2,6-trimethyl-4H-1,3-dioxin-4-one produced acetoacetanilide- containing podands. 2,2,6-Trimethyl-4H-1,3-dioxin-4-one reacted with aminoaryl-substituted podands containing a short polyether chain (1-2 atoms) in toluene medium without catalyst. Acetoacetanilide- containing podands with longer polyether chains could be obtained by using triethylamine or acetic acid as catalyst. Acetoacetanilide-containing podands were used in the Biginelli reaction as CH-active components.
- Radionova,Titova, Yu. A.,Isenov,Fedorova,Rusinov,Charushin
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p. 998 - 1004
(2015/02/05)
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- Ligand-enabled γ-C-H olefination and carbonylation: Construction of β-quaternary carbon centers
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Monoselective γ-C-H olefination and carbonylation of aliphatic acids has been accomplished by using a combination of a quinoline-based ligand and a weakly coordinating amide directing group. The reaction provides a new route for constructing richly functionalized all-carbon quaternary carbon centers at the β-position of aliphatic acids.
- Li, Suhua,Chen, Gang,Feng, Chen-Guo,Gong, Wei,Yu, Jin-Quan
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supporting information
p. 5267 - 5270
(2014/05/06)
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- Facile synthesis of furoquinoline and effects on radical-induced oxidation of DNA
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The aim of this work was to clarify the influences of the position of hydroxyl group and furo[2,3-b] moiety on the antioxidant effectiveness of quinoline. Thus, 4-methyl-2,3-dihydrofuro[2,3-b]quinolin-6-ol (PFQ), 4-methyl-2,3-dihydrofuro[2,3-b]quinolin-8-ol (OFQ), and 4-methyl-2,3- dihydrofuro[2,3-b]quinolin-7-ol (MFQ) were synthesized by a recyclization reaction of 1-acetyl-N-phenylcyclopropanecarboxamide in the presence of SnCl4 as the catalyst. The antioxidant capacities of PFQ, OFQ, and MFQ were evaluated in the experimental system of the oxidation of DNA caused by Cu2+/glutathione (GSH), ?OH, and 2,2′-azobis(2- amidinopropane hydrochloride) (AAPH). OFQ and PFQ were able to protect DNA against Cu2+/GSH- and ?OH-induced oxidation because the furo[2,3-b] moiety was beneficial for stabilizing the produced furoquinoline radical. Moreover, MFQ can decrease the oxidation rate of AAPH-induced oxidation of DNA, while PFQ and OFQ can inhibit AAPH-induced oxidation of DNA for a period. The data obtained from AAPH-induced oxidation of DNA were treated by chemical kinetic method; it was found that PFQ and OFQ can trap 1.3 and 1.5 radicals, respectively. Therefore, the hydroxyl group at different positions changed the mechanism of furoquinoline in protecting DNA against radical-induced oxidation. Graphical Abstract: Effects on Cu2+/glutathione-, ?OH-, and peroxyl radical-induced oxidation of DNA.[Figure not available: see fulltext.]
- Wang, Rui,Liu, Zai-Qun
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p. 1563 - 1569
(2013/07/26)
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- Synthesis of carbon-11-labeled casimiroin analogues as new potential PET agents for imaging of quinone reductase 2 and aromatase expression in breast cancer
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Carbon-11-labeled casimiroin analogues were first designed and synthesized as new potential PET agents for imaging of quinone reductase (QR) 2 and aromatase expression in breast cancer. [11C]casimiroin (6-[ 11C]methoxy-9-methyl-[1,3]dioxolo[4,5-h]quinolin-8(9H)-one, [ 11C]11) and its carbon-11-labeled analogues 5,6,8-trimethoxy-1-[ 11C]methyl-4-methylquinolin-2(1H)-one ([11C]17), 8-methoxy-1-[11C]methyl-4-methylquinolin-2(1H)-one ([ 11C]21a), 6,8-dimethoxy-1-[11C]methyl-4-methylquinolin- 2(1H)-one ([11C]21b), and 5,8-dimethoxy-1-[11C]methyl-4- methylquinolin-2(1H)-one ([11C]21c), were prepared from their corresponding precursors with [11C]methyl triflate ([ 11C]CH3OTf) under basic conditions (NaH) through either O- or N-[11C]methylation and isolated by semi-preparative HPLC method in 40-50% radiochemical yields decay corrected to end of bombardment (EOB), based on [11C]CO2, and 111-185 GBq/μmol specific activity at the end of synthesis (EOS).
- Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.,Zheng, Qi-Huang
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experimental part
p. 967 - 973
(2010/10/05)
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- Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent
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We have studied earlier a membrane bound novel enzyme Acetoxy Drug: protein transacetylase identified as Calreticulin Transacetylase (CRTAase) that catalyzes the transfer of acetyl groups from polyphenolic acetates (PAs) to the receptor proteins and thus modulating their biological activities. In this communication, we have reported for the first time that acetoxy quinolones are endowed with antiplatelet action by virtue of causing CRTAase catalyzed activation of platelet Nitric Oxide Synthase (NOS) by way of acetylation leading to the inhibition of ADP/Arachidonic acid (AA)-dependent platelet aggregation. The correlation of specificity of platelet CRTAase to various analogues of acetoxy quinolones with intracellular NO and consequent effect on inhibition of platelet aggregation was considered crucial. Among acetoxy quinolones screened, 6-AQ (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate/6-acetoxyquinolin-2-one, 22) was found to be the superior substrate to platelet CRTAase and emerged as the most active entity to produce antiplatelet action both in vitro and in vivo. 6-AQ caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2) and the inhibition of platelet aggregation. Structural modification of acetoxy quinolones positively correlated with enhancement of intracellular NO and antiplatelet action.
- Priya, Nivedita,Gupta, Anjali,Chand, Karam,Singh, Prabhjot,Kathuria, Abha,Raj, Hanumantharao G.,Parmar, Virinder S.,Sharma, Sunil K.
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experimental part
p. 4085 - 4094
(2010/08/06)
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- Synthesis of casimiroin and optimization of its quinone reductase 2 and aromatase inhibitory activities
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An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogues has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.
- Maiti, Arup,Reddy, P. V. Narasimha,Sturdy, Megan,Marler, Laura,Pegan, Scott D.,Mesecar, Andrew D.,Pezzuto, John M.,Cushman, Mark
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experimental part
p. 1873 - 1884
(2009/12/31)
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- Knorr cyclizations and distonic superelectrophiles
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(Chemical Equation Presented) The acid-catalyzed Knorr cyclization has been studied by experimental and theoretical methods. The results of these studies indicate that β-ketoamides such as acetoacetanilide undergo diprotonation at the two carbonyl oxygen atoms to form distonic superelectrophiles. Direct observation of a dicationic superelectrophile was achieved by low-temperature 1H, 15N, and 13C NMR from FSO 3H-SbF5-SO2ClF solutions. In synthetic studies, the Bronsted superacid CF3SO3H is found to be an effective acid catalyst for the Knorr cyclization.
- Sai, Kiran Kumar Solingapuram,Gilbert, Thomas M.,Klumpp, Douglas A.
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p. 9761 - 9764
(2008/03/27)
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- THERAPEUTIC AGENTS I
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Compounds of formula(I), processes for preparing such compounds, their use in the treatment of obesity, psychiatric disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease and pain related disorders, and pharmaceutical compositions containing them.
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Page/Page column 43
(2010/02/12)
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- Photodecomposition of Pigment Yellow 74, a pigment used in tattoo inks
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Tattooing has become a popular recreational practice among younger adults over the past decade. Although some of the pigments used in tattooing have been described, very little is known concerning the toxicology, phototoxicology or photochemistry of these pigments. Seven yellow tattoo inks were obtained from commercial sources and their pigments extracted, identified and quantitatively analyzed. The mono- azo compound Pigment Yellow 74 (PY74; CI 11741) was found to be the major pigment in several of the tattoo inks. Solutions of commercial PY74 in tetrahydrofuran (THF) were deoxygenated using argon gas, and the photochemical reaction products were determined after exposure to simulated solar light generated by a filtered 6.5 kW xenon arc lamp. Spectrophotometric and high-pressure liquid chromatography (HPLC) analyses indicated that PY74 photodecomposed to multiple products that were isolated using a combination of silica chromatography and reversed-phase HPLC. Three of the major photodecomposition products were identified by nuclear magnetic resonance and mass spectrometry as N-(2-methoxyphenyl)-3-oxobutanamide (o-acetoacetanisidide), 2-(hydroxyimine)-N-(2-methoxyphenyl)-3-oxobutanamide and N,N″-bis(2- methoxyphenyl)urea. These results demonstrate that PY74 is not photostable in THF and that photochemical lysis occurs at several sites in PY74 including the hydrazone and amide groups. The data also suggest that the use of PY74 in tattoo inks could potentially result in the formation of photolysis products, resulting in toxicity at the tattoo site after irradiation with sunlight or more intense light sources.
- Cui, Yanyan,Spann, Andrew P.,Couch, Letha H.,Gopee, Neera V.,Evans, Frederick E.,Churchwell, Mona I.,Williams, Lee D.,Doerge, Daniel R.,Howard, Paul C.
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p. 175 - 184
(2007/10/03)
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- Acetoacetarylamides
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Novel acetoacetarylamides in the form of a solidified melt which are in a form which can be used in industry and is easy to handle and which has a water content of from 3 to 15 percent by weight. These novel acetoacetarylamides have been used for the preparation of colored pigments or agrochemical active ingredients.
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- A comparative study of synthetic approach to 1-methyl-2,5,8(1H)-quinolinetrione and 4-methyl-2,5,8(1H)-quinolinetrione
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The best overall yield for 1-methyl-2,5,8(1H)-quinolinetrione was obtained by the dichromate oxidation of 1-methyl-8-hydroxy-2-quinolone. 4-Methyl-2,5,8(1H)-quinolinetrione was synthesized by acetoacetylation of 2,5-dimethoxyaniline with 2,2,6-trimethyl-4H-1,3-dioxin-4-one followed by oxidation with ceric ammonium nitrate.
- Avendano,De la Cuesta,Gesto
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p. 727 - 730
(2007/10/02)
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- Process for improving the application properties of disazo pigments
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Process for improving the application properties of disazo pigments obtained by coupling bis-diazotized chlorine-substituted 4,4'-diaminobiphenyls with acetoacetylaminobenzenes, which includes adding sulfite ions to the pigment suspension obtained in the coupling and then heating for one half to two hours at 50° to 100° C. The process produces, above all in large scale industrial batches, a product of uniform quality and having acceptable fastness to solvents, overlacquering, migration and bleeding.
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- Cyclocondensations of Acetoacetanilides with 1,3,5-Trinitrobenzene-Substituent Effect in the Formation of Bicyclononane Derivatives
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Kinetics of cyclicondensation reaction of acetoacetanilide and substituted acetoacetanilides with 1,3,5-trinitrobenzene in the presence of triethylamine have been studied in 75percentDMSO-water(v/v) at 30, 35 and 40 deg C.Electron donating groups accelerate the rate of the reaction.Strongly electron withdrawing groups in the para-position require the use of ?--values for a better correlation of the rate constants.The reaction constants and the resonance parameters have been calculated.Isokinetic relationship has been established.Equilibrium constants for the formationof sodium salts of bicyclononane derivatives from sodium salts of acetoacetanilides and TNB have been calculated.
- Gnanadoss, Lalitha,Radha, N.
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p. 1077 - 1081
(2007/10/02)
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