- The self-association of the drug acemetacin and its interactions and stabilization with beta-cyclodextrin in aqueous solution as inferred from NMR spectroscopy and HPLC studies.
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Strongly concentration dependent, (1)H NMR chemical shifts of the non-steroidal anti-inflammatory drug acemetacin sodium salt (sodium [[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetoxy]acetate), were observed in aqueous solution. Self-titration and nOe experiments, point to a self-association model where stacking takes place via the indole portion of the drug. In addition, conformational isomerism (atropisomerism) of the anti to syn form was confirmed. Further increase of the concentration eventually led to stable chemical shifts and nearly simultaneous appearance of microcrystals. In the presence of betaCD, 1:1 inclusion complexation occurred through the p-chlorobenzoyl part of the drug, whereas with excess betaCD the indole part seemed to participate to a minor degree. The anti isomer is suggested to be involved in the inclusion process. In addition, aggregation of acemetacin was also evident, as competing with the conformational and inclusion equilibria. The present case demonstrates that many competitive processes are simultaneously active in a seemingly simple system. The measurements were strongly dependent upon the pH and use of buffered solutions was mandatory. Finally, for the quantitative analysis of acemetacin in the presence of betaCD, a special HPLC method was developed. The stability of the drug, studied by the identification of the degradation products and the pseudo-first order rate of hydrolysis, was found to be unaffected by the presence of betaCD.
- Zouvelekis, Dimitris,Yannakopoulou, Konstantina,Mavridis, Irene M,Antoniadou-Vyza, Ekaterini
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- 1-Phenyl-1H-indole derivatives as a new class of Bcl-2/Mcl-1 dual inhibitors: Design, synthesis, and preliminary biological evaluation
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Bcl-2 proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, has been implicated in the progression and survival of multiple tumor types and become a validated and attractive target for cancer therapy. In this work, a series of 1-phenyl-1H-indole derivatives has been designed and synthesized. The preliminary biological studies (binding assay for Bcl-2 proteins and MTT assay) suggested that some active compounds showed potent inhibitory activities on Bcl-2/Mcl-1 without binding on Bcl-XL. Furthermore, Compound 9c and 9h showed better anti-proliferative activity than WL-276.
- Xu, Guangsen,Liu, Tingting,Zhou, Yi,Yang, Xinying,Fang, Hao
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- Hydrolysis mechanisms for indomethacin and acemethacin in perchloric acid
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The acid-catalyzed hydrolysis reactions of the antiinflammatory drugs indomethacin and acemethacin were investigated at 25.0 °C in a number of strongly concentrated perchloric acid media. The reaction rates were evaluated by UV measurements, and the intermediate species were detected by UV-vis, 1H NMR, 13C NMR, and mass spectroscopy measurements. A switchover from an A-2 to an A-1 mechanism as a function of the medium acidity is reported for the acid-catalyzed hydrolyses of the amide group of both indomethacin and acemethacin. In the A-2 hydrolysis, two water molecules are involved in the rate-determining step. An analysis of the kinetic data collected for acemethacin by the different techniques used reveals a complex mechanism, indomethacin being a metabolite intermediate species in the hydrolysis of acemethacin. The rate constants for the hydrolysis of the acemethacin ester group were considerably larger compared to those of the amide group.
- Garcia,Hoyuelos,Ibeas,Leal
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- Indole compounds with: N-ethyl morpholine moieties as CB2 receptor agonists for anti-inflammatory management of pain: Synthesis and biological evaluation
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The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with N-ethyl morpholine moieties (compounds 1-56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 53 exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50(CB1)/EC50(CB2) greater than 1000). The most active compound, compound 2, was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound 2 had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound 2 had a dose-dependent reversal for hyperalgesia with an estimated ED50 value of 1.097 mg kg-1. Moreover, compound 2 significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound 2 on inflammatory pain were superior to those of GW405833, suggesting that compound 2 may be a promising therapeutic drug that needs further validation.
- Ji, Jing,Li, Jiaojiao,Li, Zhengfu,Xu, Ruibo
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p. 1935 - 1947
(2019/11/20)
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- Pd-tBuONO Cocatalyzed Aerobic Indole Synthesis
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A Pd-tBuONO co-catalyzed scalable and practical synthesis of indoles with molecular oxygen as terminal oxidant is developed. Either terminal or internal 2-vinylanilines could be smoothly converted to desired indoles under one general condition. This method has been evaluated in the large scale synthesis of indomethacin and a potential anti-breast cancer drug candidate 1. (Figure presented.).
- Ning, Xiao-Shan,Liang, Xin,Hu, Kang-Fei,Yao, Chuan-Zhi,Qu, Jian-Ping,Kang, Yan-Biao
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p. 1590 - 1594
(2018/04/30)
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- Synthesis of Functionalized Indoles via Palladium-Catalyzed Aerobic Cycloisomerization of o-Allylanilines Using Organic Redox Cocatalyst
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A scalable and practical synthesis of functionalized indoles via Pd-tBuONO cocatalyzed aerobic cycloisomerization of o-allylanilines is reported. Using molecular oxygen as a terminal oxidant, a series of substituted indoles were prepared in moderate to good yields. The avoidance of hazardous oxidants, heavy-metal cocatalysts, and high boiling point solvents such as DMF and DMSO enables this method to be applied in pharmaceutical synthesis. A practical gram-scale synthesis of indomethacin demonstrates its application potential.
- Ning, Xiao-Shan,Wang, Mei-Mei,Qu, Jian-Ping,Kang, Yan-Biao
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p. 13523 - 13529
(2018/10/25)
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- Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase
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We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development.
- Raji, Idris,Yadudu, Fatima,Janeira, Emily,Fathi, Shaghayegh,Szymczak, Lindsey,Kornacki, James Richard,Komatsu, Kensei,Li, Jian-Dong,Mrksich, Milan,Oyelere, Adegboyega K.
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p. 1202 - 1218
(2017/02/05)
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- Synthesis of novel indole-benzimidazole derivatives
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2-Methylindole-3-acetic acid and its 5-methoxy derivative were prepared from the respective phenylhydrazines and levulinic acid. Indole-3-carboxylic acid was obtained from indole, dimethylformamide and trifluoroacetic acid. These indole carboxylic acids were then condensed with substituted o-phenylenediamines under high temperature conditions in the presence of polyphosphoric acid as a catalyst to give the combined indole-benzimidazoles.
- Wang, Xinying,Liu, Yizhou,Xu, Juan,Jiang, Fanwei,Kang, Congmin
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p. 588 - 590
(2016/10/18)
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- Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans
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Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase- and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms.
- Xie, Gang,Zhou, Dingying,Cheng, Ka-Wing,Wong, Chi C.,Rigas, Basil
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p. 1195 - 1202
(2013/05/22)
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- Ortho-Carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors
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A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.
- Scholz, Matthias,Blobaum, Anna L.,Marnett, Lawrence J.,Hey-Hawkins, Evamarie
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supporting information; experimental part
p. 4830 - 4837
(2012/09/22)
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- Discovery of selective indole-based prostaglandin D2 receptor antagonist
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A series of N-benzoyl-2-methylindole-3-acetic acids were synthesized and biologically evaluated as prostaglandin (PG) D2 receptor antagonists. Some of the selected compounds significantly inhibited OVA-induced vascular permeability in guinea pig conjunctiva after oral dosing. Structure-activity relationship study is presented.
- Iwahashi, Maki,Shimabukuro, Atsushi,Onoda, Takahiro,Matsunaga, Yoko,Okada, Yutaka,Matsumoto, Ryoji,Nambu, Fumio,Nakai, Hisao,Toda, Masaaki
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p. 4574 - 4588
(2011/09/19)
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- A General Synthesis of Substituted Indoles from Cyclic Enol Ethers and Enol Lactones
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(Equation presented) A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives. This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.
- Campos, Kevin R.,Woo, Jacqueline C. S.,Lee, Sandra,Tillyer, Richard D.
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- Effect of Liposomes on the Rate of Alkaline Hydrolysis of Indomethacin and Acemetacin
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The anti-inflammatory, analgesic, and antipyretic drugs indomethacin (INDO) and acemetacin (ACE), extensively used for the treatment of diseases of degenerative or inflammatory character, exhibit marked gastric irritant action, have low water solubility at neutral pH, and decompose in alkali. Alternative formulations are being investigated to obtain products with lower toxicity and higher stability. Here we examine the effect of liposome charge on the rate of alkaline decomposition of INDO and ACE using micelles as reference. Binding of ACE and INDO to zwitterionic hexadecylphosphocholine (HDPC) micelles and phosphatidylcholine (PC) liposomes was analyzed using a two-phase separation model to quantify the effect of these aggregates on the rate of alkaline degradation. The substrate association constants to HDPC micelles were 1335 and 2192 M-1 for INDO and ACE, respectively, whereas the corresponding values for PC vesicles were 612 and 3050 M-1. The difference was attributed to the additional hydrophobicity of ACE. The inhibitory effect of HDPC micelles and PC vesicles was quantified by calculating the ratio between the rate constants in water (kw) and in the aggregate (km). The values of the kw/km ratios for INDO and ACE in HDPC micelles were, respectively, 80 and 42, and in PC liposomes these ratios were 21 and 3.7, respectively. Positively charged micelles of hexadecyltrimethylammonium chloride (CTAC) and vesicles containing varying proportions of dioctadecyldimethylammonium chloride (DODAC) and PC increase the rate of INDO and ACE alkaline decomposition. Vesicle effects were very sensitive to the DODAC/PC ratio, with rates increasing with the proportion of DODAC. The data were analyzed quantitatively using a pseudophase model with explicit consideration of ion exchange. The calculated second-order rate constants in micelles and vesicles were lower than that in water. The charge density in the liposome necessary to increase the entrapment efficiency and decrease drug decomposition can be modulated, by judicious choice of pH and ionic strength. These manipulations can lead to more stable formulation with increased efficiency in drug entrapment and controlled effects on drug stability.
- Matos, C.,Chaimovich, H.,Lima, J. L. F. C.,Cuccovia, I. M.,Reis, S.
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p. 298 - 309
(2007/10/03)
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- New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents
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A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2- decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3- yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 μM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 μM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 μM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin- induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 μM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.
- Menciu, Cecilia,Duflos, Muriel,Fouchard, Fabienne,Le Baut, Guillaume,Emig, Peter,Achterrath, Ute,Szelenyi, Istvan,Nickel, Bernd,Schmidt, Jürgen,Kutscher, Bernhard,Günther, Eckhardt
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p. 638 - 648
(2007/10/03)
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- Substituent Effects on the Spectral, Acid-Base, and Redox Properties of Indolyl Radicals: A Pulse Radiolysis Study
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Spectral and acid-base properties and reduction potentials of various substituted indolyl radicals were studied by pulse radiolysis in aqueous solutions at 20 deg C.Except for the 5-methoxyindolyl and 5-carboxyindolyl radicals, the spectra of the substituted indolyl radicals resemble the previously published 320- and 520-nm spectra of the neutral and 330- and 580-nm spectra of the cation indolyl and tryptophan radicals.The substitution of indolyl radical cation by electron-attracting groups (positive ?+) results in a blue shift of the 580-nm band by ca. 30 nm,, whereas the spectra of methylindolyl (?+ = -0.31) are similar to those of unsubstituted indolyl radicals.The 430- and 455-nm bands appearing in the spectra of the 5-carboxyindolyl and 5-methoxyindolyl radical cations, respectively, indicate even stronger interaction of the unpaired electron with the 5-substituent.The radical cations of various indole-3-acetic acids decarboxylate at pH values below their pKa to produce allyl radicals.The 5-bromoindolyl radical undergoes solvolysis to 5-hydroxyindolyl radical in acidic and alkaline media.The dissociation constants and reduction potentials of the substituted indolyl radicals correlate with the Brown substituent constants: pKr = 4.14 - 2.13Σ?+, correlation coefficient 0.987, and E0/0.059 = 22.29 + 3.5Σ?+, correlation coefficient 0.980.The ρ values from these correlations (-2.13 and 3.5) are similar to that of the Hammett correlation of the dissociation constants of the protonated indole nitrogen in various substituted indoles, ρ = -2.49, but smaller than the ρ value of the dependence on the substituent of the reduction potentials of phenoxyl radicals, ρ = 5.4.
- Jovanovic, Slobodan V.,Steenken, Steen
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p. 6674 - 6679
(2007/10/02)
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- C-Alkylations of Indoles and Pyrroles with α-Chloro Sulfides on an Alumina Surface: A Short Synthesis of Dithyreanitrile
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Alumina-mediated C-alkylations of indoles and pyrroles with α-chloro sulfides have been examined.Thus, a mixture of indoles 1 and the α-chloro sulfides 2 or 3, on treatment with neutral alumina, gave the ethyl indol-3-ylacetates 5 and the corresponding acetonitriles 6, respectively.A similar reaction of the chloride 4 wih 7-methoxyindole provided direct access to dithyreanitrile 7h, which is an insect antifeedant.The pyrrole 10 was also allowed to react with α-chloro sulfides 2 and 3 to afford the 2-substituted products 11 and 12, respectively.On the other hand, the reactions of skatole 14 with 2 and 3 gave the 2-alkylation products 15 and 16, respectively, but in low yields.However, 2,3-dimethylindol 17 reacted smoothly with 2 and 3 to give the indolenines 18 and 19, respectively.The reaction of 2,5-dimethylpyrrole 25 with 2 afforded the 2,2,5-trisubstituted 2H-pyrrole 26 as a major product along with the 2,3,5-trisubstituted 1H-pyrrole 27.Some chemical transformations of the products 5, 18 and 26 are also described.
- Ishibashi, Hiroyuki,Mita, Naoki,Matsuba, Naoko,Kubo, Tomoko,Nakanishi, Mariko,Ikeda, Masazumi
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p. 2821 - 2826
(2007/10/02)
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- Micellar effects on the basic hydrolysis of indomethacin and related compounds
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The kinetics of hydrolysis of indomethacin and related compounds was studied in an alkaline medium at 25°C in the presence of anionic (sodium dodecyl sulfate) and cationic (hexadecyltrimethylammonium bromide) surfactants. The rate-surfactant profiles for rate inhibition in the presence of sodium dodecyl sulfate and rate enhancement in the presence of hexadecyltrimethylammonoium bromide were analyzed in terms of the current theory of micellar effects.
- Cipiciani,Ebert,Germani,Linda,Lovrecich,Rubessa,Savelli
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p. 1184 - 1187
(2007/10/02)
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- Kinetics and mechanism of the basic hydrolysis of indomethacin and related compounds: A reevaluation
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The kinetics of the hydrolysis of indomethacin and related compounds were studied in an alkaline medium at 25°. The pseudo-first-order rate constants were evaluated from log absorbance versus time plots in the ultraviolet. These compounds showed a second-order rate constant at low concentrations of hydroxide ion and a first-order rate constant at higher concentrations of hydroxide ion.
- Cipiciani,Ebert,Linda,Rubessa,Savelli
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p. 1075 - 1076
(2007/10/02)
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