- Studies on the adsorption and photocatalytic degradation of an EuIII(TTFA)3(MePhTerpy) complex on the TiO2 surface
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The luminescent dye EuropiumIII(thenoyltrifluoroacetone)(4′-(4-methylphenyl)-2,2′:6′,2′′-terpyridine) (EuIII(TTFA)3(MePhTerpy)) has been proposed as a probe molecule for a fast photocatalytic test of TiO2-materials. For an industrial application of this test method the underlying photocatalytic reaction mechanism and the degradation products of the dye need to be known. Hence, in this study the adsorption and the photocatalytic degradation of the luminescent dye on the TiO2 surface were investigated by means of ATR-FTIR spectroscopy and GC/MS analysis. The dye is adsorbed by the thenoyltrifluoroacetone (TTFA) ligand on the TiO2 surface as evinced by the respective ATR-FTIR spectra. It is assumed that TTFA and TiO2 form hydrogen bonds. Upon UV illumination the ATR-FTIR spectra reveal a degradation of the TTFA ligand forming trifluoroacetic acid (TFAA) and 2-thiophenecarboxylic acid (TCA). GC/MS analysis confirms the ATR-FTIR results because TCA and TFAA are also detected here. Additionally, 2-thiophenecarboxaldehyde is observed, which is proposed to be an intermediate that is further oxidized to TCA.
- Melchers, Stephanie,Alsalka, Yamen,Schneider, Jenny,Bahnemann, Detlef W.
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Read Online
- An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors
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Integrated continuous manufacturing has emerged as a promising device for the rapid manufacturing of active pharmaceutical ingredients (APIs). We herein report a newly designed continuous flow micro-total process system platform for the rapid manufacturing of celecoxib, a selective nonsteroidal anti-inflammatory drug. This approach has been proven generally for the synthesis of several alkyl and aryl substituted pyrazoles. In order to minimize the tedious work-up process of potential reaction intermediates/products, we have developed a continuous flow extraction and separation platform to carry out the entire reaction sequence resulting in a short residence time with good yield. The present process was further extended to gram-scale synthesis of the COX-2-related API, viz. celecoxib, in the continuous flow process.
- Sthalam, Vinay Kumar,Singh, Ajay K.,Pabbaraja, Srihari
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supporting information
p. 1892 - 1899
(2019/10/11)
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- Discovery and structure-resistance relationship study of new thieno[2,3-b] pyridine HCV NS4B inhibitors
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The non-structural protein 4B (NS4B) of hepatitis C virus (HCV) has emerged as a promising target for chronic hepatitis C treatment. The thieno[2,3-b]pyridine HCV inhibitor 2 has demonstrated properties as a NS4B inhibitor. Subsequent hybridization of 2 with our recently published imidazo[2,1-b]thiazole NS4B inhibitor 3 resulted in the discovery of several more potent compounds with sub-micromolar EC50 against HCV genotype 1b replicon. More importantly, the resistant profile study of the new synthesized HCV inhibitors illustrated that the bicyclic scaffold would mediate the resistance of H3R and Q26R mutations, while the piperazinone motif would mediate the resistance of H94R, F98C and V105M mutations, and the C3- amino group would disrupt the interaction between piperazinone motif and NS4B. This structure-resistance relationship detail could help us to develop new NS4B inhibitors with higher resistant barrier in the future.
- Xiao, Kun-Jie,Zuo, Wei-Qiong,Xu, Ying,Tao, Xin,Yu, Luo-Ting,Wang, Ning-Yu
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p. 321 - 325
(2019/08/22)
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- APOPTOSIS INHIBITORS
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The invention provides compounds that are inhibitors or covalent modifiers of succinate dehydrogenase subunit B (SDHB) and/or inhibitors of apoptosis, and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.
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Paragraph 0122
(2018/02/27)
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- Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
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In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-7j were prepared in one pot manner via enaminone intermediate using novel methodology. All the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of edema related isoform hCA I with their inhibition constant (Ki) ranging from 30.1 to 86.8 nM as compared to standard drug acetazolamide (AAZ) with Ki = 250 nM. Further it was found that most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b, 7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition potential (Ki i = 52.4 nM) than AAZ (Ki = 74 nM) while against tumor associated hCA IX, all the compounds have shown moderate inhibition potential. Present study have added one more step in exploring the 1,2,3-triazlole moiety in the medicinal field.
- Kumar, Rajiv,Vats, Lalit,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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p. 545 - 551
(2018/06/18)
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- Discovery and structure-activity relationships study of thieno[2,3-b]pyridine analogues as hepatic gluconeogenesis inhibitors
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Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC50 = 33.8 μM) characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF3 in the thienopyridine core could improve the potency and led to the discovery of 8e (IC50 = 16.8 μM) and 9d (IC50 = 12.3 μM) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents.
- Ma, Fei,Liu, Jian,Zhou, Tingting,Lei, Min,Chen, Jing,Wang, Xiachang,Zhang, Yinan,Shen, Xu,Hu, Lihong
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p. 307 - 317
(2018/05/22)
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- Discovery of Highly Potent 2-Sulfonyl-Pyrimidinyl Derivatives for Apoptosis Inhibition and Ischemia Treatment
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A series of 2-sulfonyl-pyrimidinyl derivatives was developed as apoptosis inhibitors. These represent the first class of apoptosis inhibitors that function through stabilizing mitochondrial respiratory complex II. Starting from a phenotypic screen hit with micromolar activity, we optimized the cellular apoptosis inhibition activity of 2-sulfonyl-pyrimidinyl derivatives to picomolar level (compound 42, also named as TC9-305). The therapeutic potential of these new apoptosis inhibitors was further demonstrated by their neuroprotective effect on an ischemic animal model.
- Li, Li,Jiang, Xian,Huang, Shaoqiang,Ying, Zhengxin,Zhang, Zhaolan,Pan, Chenjie,Li, Sisi,Wang, Xiaodong,Zhang, Zhiyuan
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supporting information
p. 407 - 412
(2017/04/21)
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- A Sequential Route to Cyclopentenes from 1,6-Enynes and Diazo Ketones through Gold and Rhodium Catalysis
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This work reports the construction of cyclopentene cores from 1,6-enynes and aryl diazo ketones through two new reaction sequences involving initial gold-catalyzed cyclization of 1,6-enynes with diazo species, followed by rhodium-catalyzed skeletal rearrangement of the resulting 3-cyclopropyl-2-en-1-ones. In most instances the rhodium-catalyzed reactions afforded cyclopentene derivatives whereas several n-alkyl- or ortho-substituted phenyl ketones delivered seven-membered oxacycles. A plausible mechanism provides rationales for these two distinct products. (Figure presented.).
- Kale, Balaji S.,Lee, Hsin-Fu,Liu, Rai-Shung
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supporting information
p. 402 - 409
(2017/02/10)
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- 1,5-Diketones Synthesis via Three-Component Cascade Reaction
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A mild and efficient cascade synthesis of 1,5-diketones from readily available N,N-dicyclohexylmethylamine, 1,3-dicarbonyl compounds, and trifluoromethyl β-diketones has been developed. This cascade reaction occurs via an oxidation/Mannich reaction/Cope elimination/Michael addition/retro-Claisen reaction sequence, and provides multiple C-C bond formations in one pot. In addition, exquisite chemoselectivity is achieved in the reaction between 1,3-dicarbonyl compounds and trifluoromethyl β-diketones.
- Xing, Li-Juan,Lu, Tao,Fu, Wei-Li,Lou, Mei-Mei,Chen, Bo,Wang, Zhi-Shen,Jin, Yang,Li, Dan,Wang, Bin
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supporting information
p. 3076 - 3080
(2015/11/03)
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- Discovery and structure-activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors
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Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50 = 3.3 μM, SI >30.3, 12b, EC50 = 3.5 μM, SI >28.6, 10l, EC50 = 3.9 μM, SI >25.6, 12o, EC 50 = 4.5 μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents.
- Wang, Ning-Yu,Zuo, Wei-Qiong,Xu, Ying,Gao, Chao,Zeng, Xiu-Xiu,Zhang, Li-Dan,You, Xin-Yu,Peng, Cui-Ting,Shen, Yang,Yang, Sheng-Yong,Wei, Yu-Quan,Yu, Luo-Ting
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supporting information
p. 1581 - 1588
(2014/03/21)
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- Comparative study of the regioselectivity and reaction media for the synthesis of 1-tert-butyl-3(5)-trifluoromethyl-1H-pyrazoles
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A study is presented for the synthesis of a series of 1-tert-butyl-3(5)- (trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3- alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Et and R 1 = H or R = Me and R1 = Me, Ph, 4-Me-C6H 4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C 6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)- trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H- pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, followed by cyclization in [BMIM][BF4] and pyridine.
- Martins, Marcos A. P.,Marzari, Mara R. B.,Frizzo, Clarissa P.,Zanatta, Marcileia,Buriol, Lilian,Andrade, Valquiria P.,Zanatta, Nilo,Bonacorso, Helio G.
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p. 7112 - 7119
(2013/02/21)
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- Thienyl-containing β-diketones: Synthesis, characterization, crystal structure and keto-enol kinetics
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1-phenyl-3-(2-thenoyl)-1,3-propanedione, Hbth, pKa′ = 9.006(8) and 1,3-di(2-thenoyl)-1,3-propanedione, Hdtm, pKa′ = 8.893(3) were prepared by the Claisen condensation of ethyl 2- thiophenecarboxylate with an appropriate ketone under the influence of lithium diisopropylamide (LDA). The group electronegativity of the thienyl group is 2.10 (Gordy scale) as calculated froma linear group electronegativity vs. methyl ester IR carbonyl stretching wavenumber relationship. A crystal structure determination of Hbth (orthorhombic, Pbca, Z = 8, R = 0.0290) shows asymmetrical enolization on the side of the phenyl group. The preferred enol isomer of β-diketones containing more than one aromatic moiety that crystallizes in the solid state is determined by the resonance driving force stabilization of the thienyl or any other aromatic group, rather than the stabilization by resonance due to the phenyl group. The slow conversion of the enol isomers to the keto-enol equilibrium position was followed in CDCl3 solution by NMR spectroscopy.
- Conradie, Marrigje M.,Muller, Alfred J.,Conradie, Jeanet
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- Interactions of aroyl- and heteroaroyltrifluoroacetones with thiobenzoylhydrazine
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The interaction of aroyl(heteroaroyl)trifluoroacetones with thiobenzoylhydrazine may occur at both carbonyl groups. Reaction at the trifluoroacetyl group is facilitated by terminal substituents in the 1,3-dicarbonyl part, which leads can effectively conjugate with the adjacent carbonyl group. The products of condensation at the trifluoroacetyl group are 2-[2-aryl(heteroaroyl)-2-oxoethyl]-5-phenyl-2-trifluoromethyl-2,3-dihydro-1,3, 4-thiadiazoles, while condensation at the aroyl(heteroaroyl)group gave 3-aryl(heteroaryl)-5-hydroxy-1-thiobenzoyl-5-trifluoromethyl-4, 5-dihydro-1H-pyrazoles, which are not prone to tautomeric transformations in solution. 2008 Springer Science+Business Media, Inc.
- Pakalnis,Zerova,Yakimovitch,Alekseyev
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p. 606 - 614
(2013/07/25)
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- Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products
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Acylhydrazines react with 1,3-diketones of the general formula CF 3COCH2COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl3 as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.
- Pakal'nis,Zerova,Yakimovich
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p. 1732 - 1741
(2008/04/05)
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- Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 1: Synthesis and inhibitory activity of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides
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We synthesized and evaluated a series of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamides to identify potent inhibitors of calcium-release-activated calcium (CRAC) channels with greater selectivity than voltage-operated calcium (VOC) channels. These efforts resulted in identification of compounds 22 and 24. The former exhibits highly potent and selective CRAC channel inhibitory activity, and the latter inhibited phytohemagglutinin-induced interleukin-2 production by Jurkat T lymphocytes and concanavalin A-induced hepatitis in mice.
- Yonetoku, Yasuhiro,Kubota, Hirokazu,Okamoto, Yoshinori,Toyoshima, Akira,Funatsu, Masashi,Ishikawa, Jun,Takeuchi, Makoto,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
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p. 4750 - 4760
(2007/10/03)
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- Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 2: Synthesis and inhibitory activity of aryl-3-trifluoromethylpyrazoles
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To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure-activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration.
- Yonetoku, Yasuhiro,Kubota, Hirokazu,Okamoto, Yoshinori,Ishikawa, Jun,Takeuchi, Makoto,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
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p. 5370 - 5383
(2007/10/03)
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- Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. Part 4: Heterocycles at C3
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New indeno[1,2-c]pyrazol-4-one cyclin dependent kinase inhibitors have been disclosed. The most promising compounds are nanomolar enzyme inhibitors with excellent activity against tumor cells. The most advanced compound retains cell culture activity even in the presence of human serum proteins. The most advanced compound did not kill the normal fibroblast line AG1523.
- Yue, Eddy W.,DiMeo, Susan V.,Higley, C. Anne,Markwalder, Jay A.,Burton, Catherine R.,Benfield, Pamela A.,Grafstrom, Robert H.,Cox, Sarah,Muckelbauer, Jodi K.,Smallwood, Angela M.,Chen, Haiying,Chang, Chong-Hwan,Trainor, George L.,Seitz, Steven P.
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p. 343 - 346
(2007/10/03)
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- Kinetics and mechanism of ligand substitution in β-diketone complexes of iron(III). Solvolysis controlling the substitution process in alcohol media
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Conventional and stopped-flow spectrophotometry was used to study the kinetics of ligand substitution in a number of tris β-diketone iron(III) complexes, Fe(O∩O)3, by 8-hydroxyquinoline (=HO∩N) in alcohol media (O∩O-=anion of the β-diketones pentane-2,4-dione, 2,6-dimethylheptane-3,5-dione, 2,2,6,6-tetramethylheptane-3,5-dione, 1-phenylbutane-1,3-dione, 1,3-diphenylpropane-2,3-dione, and 1-(2-thienyl)-4,4,4-trifluorobutane-1,3-dione). As shown by spectrophotometry, the solutions of complexes Fe(O∩O)3 in alcohols ROH are subject to solvolytic dissociation, leading to solvento species Fe(O∩O)2S2 and to binuclear complexes [Fe(O∩O)2(RO)]2 (S=ROH and RO-, respectively). The reaction of complexes Fe(O∩O)3 with HO∩N in alcohol media, leading to Fe(O∩N)3, is triphasic. The corresponding first-order rate constants k1, k2, and k3 are independent of the concentration of the entering ligand HO∩N and follow the order k1>k2>k3, with k1/k2≈10 and k1/k3≈102. For a given system Fe(O∩O)3/HO∩N/ROH, the size of k1, k2, and k3 correlates with the solvent polarity parameter ET(30). Rate constant k1 describes the solvolytic dissociation of the complexes Fe(O∩O)3 and rate constant k3 the solvent-initiated splitting of the binuclear complexes [Fe(O∩O)2(RO)]2. Rate constant k2 is assigned to the solvolytic dissociation of the intermediate complex Fe(O∩O)2(O∩N). Depending on the nature of the coordinated β-diketone and solvent ROH, k1 ranges from 0.04 to 2 s-1, k2 from 0.007 to 0.2 s-1, and k3 from 0.002 to 0.01 s-1 at 298 K. The mechanism of the ligand substitution processes is discussed.
- Gumbel, Gerhard,Elias, Horst
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- Synthesis of 1,1,1-trihalo-4-methoxy-4-[2-heteroaryl]-3-buten-2-ones, the corresponding butan-1,3-dione and azole derivatives
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The synthesis of 1,1,1-trihalo-4-methoxy-4-[2-thienyl]-3-buten-2-ones, 1,1,1-trihalo-4-methoxy-4-[2-furyl]-3-buten-2-ones and the respective trihalomethyl 1,3-butanone derivatives by trihaloacylation of dimethoxy acetals derived from 2-acetylthiophene and 2-acetylfuran are reported. This is a convenient method to obtain fluorinated and chlorinated 1,3-dielectrophiles from 2-acetylthiophene and 2-acetylfuran. The fluorinated 1,3-dielectrophiles were used to synthesize five new 2-thienyl- and 2-furylazoles. The structure of all products were assigned by 1HH- and 13C NMR and mass spectrometry.
- Flores, Alex F.C,Brondani, Sergio,Zanatta, Nilo,Rosa, Adriano,Martins, Marcos A.P
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p. 8701 - 8705
(2007/10/03)
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- A convenient and regioselective synthesis of 4-trifluoromethylpyridines
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Trifluoromethyl-substituted β-diketones regioselectively react with primary enamines such as β-aminocrotononitrile and ethyl β-aminocrotonate, providing moderate to good yields of 4-trifluoromethylpyridines.
- Katsuyama,Ogawa,Yamaguchi,Funabiki,Matsui,Muramatsu,Shibata
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p. 1321 - 1324
(2007/10/03)
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- The Reactions of Zinc(II) with 1,3-Diketones in Aqueous Solution. Catalysis by Cacodylic Acid during Complex Formation
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The reactions of zinc(II) with three 1,3-diketones have been investigated in aqueous solution at 25 deg C and an ionic strength of 0.5 mol dm-3 NaClO4.The catalytic effect of cacodylic acid on the reactions of zinc(II) with pentane-2,4-dione has been demonstrated.In addition, the effect of cacodylic acid on the hydrolysis of the nickel(II) and copper(II) triglycine complexes has been investigated.
- Hynes, Michael J.,Mooney, Marie T.,Moloney, Ann
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p. 313 - 318
(2007/10/02)
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