- Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors
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We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel anticancer targeted therapies.
- Oyallon, Bruno,Brachet-Botineau, Marie,Logé, Cédric,Bonnet, Pascal,Souab, Mohamed,Robert, Thomas,Ruchaud, Sandrine,Bach, Stéphane,Berthelot, Pascal,Gouilleux, Fabrice,Viaud-Massuard, Marie-Claude,Denevault-Sabourin, Caroline
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- Uncatalyzed condensation between aryl-1,2-diamines and diethyl bromomalonate: a one-pot access to substituted ethyl 3-hydroxyquinoxaline-2-carboxylates
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A one-pot method for the synthesis of substituted ethyl 3-hydroxyquinoxaline-2-carboxylates under solvent and catalyst free conditions has been developed.
- Haldar, Pranab,Dutta, Bishnupada,Guin, Joyram,Ray, Jayanta K.
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- A highly selective fluorescent chemosensor for Mg2+ based on a diarylethene with a quinoxaline unit
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A new fluorescent probe 1O was synthesized through linking diarylethene and Quinoxaline-2-hydraqzide group, probe 1O showed a selective “off-on” fluorescent response toward Mg2+. In the presence of Mg2+, the probe 1O displayed a distinct change of fluorescence color, from dark to green, the fluorescence intensity increased 6.8-fold, and meanwhile, emission peak has a significant blue shift, which was shifted from 524 nm to 518 nm. Then, on account of the fluorescence properties of compound 1O, we designed a logic gate. On top of that, probe 1O also can be successfully used to monitor Mg2+ of the actual water samples.
- Zhang, Yaping,Li, Hui,Jiang, Duohua,Pu, Shouzhi
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- Identification of 3-(benzazol-2-yl)quinoxaline derivatives as potent anticancer compounds: Privileged structure-based design, synthesis, and bioactive evaluation in vitro and in vivo
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Inspired by the common structural characteristics of numerous known antitumor compounds targeting DNA or topoisomerase I, 3-(benzazol-2-yl)-quinoxaline-based scaffold was designed via the combination of two important privileged structure units —quinoxaline and benzazole. Thirty novel 3-(benzazol-2-yl)-quinoxaline derivatives were synthesized and evaluated for their biological activities. The MTT assay indicated that most compounds possessed moderate to potent antiproliferation effects against MGC-803, HepG2, A549, HeLa, T-24 and WI-38 cell lines. 3-(Benzoxazol- -2-yl)-2-(N-3-dimethylaminopropyl)aminoquinoxaline (12a) exhibited the most potent cytotoxicity, with IC50 values ranging from 1.49 to 10.99 μM against the five tested cancer and one normal cell line. Agarose-gel electrophoresis assays suggested that 12a did not interact with intact DNA, but rather it strongly inhibited topoisomerase I (Topo I) via Topo I-mediated DNA unwinding to exert its anticancer activity. The molecular modeling study indicated that 12a adopt a unique mode to interact with DNA and Topo I. Detailed biological study of 12a in MGC-803 cells revealed that 12a could arrest the cell cycle in G2 phase, inducing the generation of reactive oxygen species (ROS), the fluctuation of intracellular Ca2+, and the loss of mitochondrial membrane potential (ΔΨm). Western Blot analysis indicated that 12a-treatment could significantly up-regulate the levels of pro-apoptosis proteins Bak, Bax, and Bim, down-regulate anti-apoptosis proteins Bcl-2 and Bcl-xl, and increase levels of cyclin B1 and CDKs inhibitor p21, cytochrome c, caspase-3, caspase-9 and their activated form in MGC-803 cells in a dose-dependent manner to induce cell apoptosis via a caspase-dependent intrinsic mitochondria-mediated pathway. Studies in MGC-803 xenograft tumors models demonstrated that 12a could signi?cantly reduce tumor growth in vivo at doses as low as 6 mg/kg with low toxicity. Its convenient preparation and potent anticancer efficacy in vivo makes the 3-(benzazol-2-yl)quinoxaline scaffold a promising new chemistry entity for the development of novel chemotherapeutic agents.
- Liu, Qing-Qing,Lu, Ke,Zhu, Hai-Miao,Kong, Shi-Lin,Yuan, Jing-Mei,Zhang, Guo-Hai,Chen, Nan-Ying,Gu, Chen-Xi,Pan, Cheng-Xue,Mo, Dong-Liang,Su, Gui-Fa
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- 3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis
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Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-A
- Chen, Nan-Ying,Lu, Ke,Yuan, Jing-Mei,Li, Xiao-Juan,Gu, Zi-Yu,Pan, Cheng-Xue,Mo, Dong-Liang,Su, Gui-Fa
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- Synthesis, EGFR-TK inhibition and anticancer activity of new quinoxaline derivatives
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Ethyl 4-substituted-3-oxo-quinoxaline-2-carboxylates 3–5 were obtained via alkylation of ethyl 3-oxo-3,4-dihydroquinoxaline-2-carboxylate (1). Compound 1 was heterocyclized using hydrazines, ethylenediamine, and ethanolamine to give pyrazoloquinoxalines 6, 7, diazepinoquinoxaline 8, and oxazepinoquinoxaline 10. The quinoxaline-2-carboxamides 9, 11, 12 were prepared via condensation of compound 1 with different amines. Compound 1 was thiated using Lawesson’s reagent affording quinoxaline-3-thione 13, in fair yield. In addition, the reaction of 4-methyl-3-oxoquinoxaline 3 with some binucleophiles led to a series of new oxoquinoxaline derivatives 14–18. The molecular structure of compounds 1, 3, and 9 was confirmed by X-ray crystallography. The anti-proliferative activity showed that among all the tested compounds, compounds 3, (IC50 2.51 ± 3.0, 4.22 ± 1.6 and 2.27 ± 1.9 μM), 11 (IC50 1.32 ± 2.61, 1.41 ± 1.23 and 1.18 ± 1.91 μM) and 17 (IC50 1.72 ± 1.32, 1.85 ± 0.94 and 1.92 ± 4.83 μM) showed noteworthy anti-proliferative effects against the three cancer cell lines, HCT116, HePG2 and MCF7, respectively, compared to the reference drugs doxorubicin (IC50 1.41 ± 0.58, 0.90 ± 0.62 and 1.01 ± 3.02 μM) and erlotinib (IC50 1.63 ± 0.81, 1.57 ± 0.62 and 1.49 ± 0.54 μM). Compounds 3 (0.899 nM), 11 (0.508 nM) and 17 (0.807) showed strong EGFR inhibitory activity compared to Erlotinib (0.439 nM) and these results are in agreement with the docking study. These results suggest that compounds could probably be promising anticancer agents with EGFR inhibitory activity.
- Ahmed, Eman A.,Mohamed, Mamdouh F. A.,Omran, Ahmed,Salah, Hanan
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supporting information
p. 2924 - 2940
(2020/07/13)
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- 2-(omega-dialkylamino)aminoalkyl-3-aryloxazolequinoxaline compounds as well as preparation method and application thereof
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The invention discloses 2-(omega-dialkylamino)aminoalkyl-3-aryloxazolequinoxaline compounds as well as a preparation method and application thereof, and specially relates to a pharmaceutical composition containing the compounds, and an application in preparation of antitumor and topoisomerase I inhibiting drugs. The compounds disclosed by the invention have a good inhibitory effect on topoisomerase I, and exhibit good antitumor effects in vitro and in vivo.
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Paragraph 0060; 0061; 0062
(2018/09/26)
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- Synthesis of 2-(Quinoxalin-2-ylamino-benzotriazolyl) Pentanedioic Derivatives as Potential Anti-Folate Agents
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Anti-folate agents had a significant impact on therapeutic treatment plans for diseases such as cancer, and bacterial and parasitic infections, notably malaria. Quinoxaline derivatives showed in vitro anticancer activity and were able to inhibit both the dihydrofolate reductase and thymidylate synthase. Here, we decided to combine the chemical properties of quinoxalines and quinoxaline 1,4-dioxides with those of benzotriazole nucleus with the aim to evaluate the resulting biological properties. Two main new series, including more than 60 compounds, were prepared. In the first one, the benzotriazole moiety was linked through the nitrogen atoms 1, 2, or 3, to a glutaric acid substituent to simulate a glutamic moiety. In the second series, the glutaric acid was substituted with acetic acid moiety to evaluate the effects of steric hindrance. Here, we describe the multistep chemical processes to obtain all titled quinoxalines starting from commercially available diamines. The classical oxidation of selected quinoxalines was unsuccessful, and we have come to an independent synthetic pathway to obtain new derivatives linked to the benzotriazole moieties starting from synthons bearing N-oxide functionality.
- Briguglio,Piras,Corona,Pirisi,Burrai,Boatto,Gavini,Rassu
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p. 1721 - 1737
(2016/11/23)
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- Synthesis of multisubstituted dihydroquinoxaline derivatives by tandem N-alkylation and addition reactions of 3-oxoquinoxaline-2-carboxylates
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This report describes a one-pot synthesis of multisubstituted dihydroquinoxalin-2-ones using an umpolung N-alkylation followed by oxidation and C-alkylation reactions. Moreover, the synthesis of tricyclic compounds containing a dihydroquinoxaline skeleton was carried out by ring closing metathesis (RCM) of the resulting N,C-bis-addition products containing olefins.
- Miyamaru, Satoru,Umezu, Kazuto,Ito, Akinori,Shimizu, Makoto
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supporting information
p. 3327 - 3337
(2015/05/20)
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- Ligand-based design, synthesis, and pharmacological evaluation of 3-methoxyquinoxalin-2-carboxamides as structurally novel serotonin type-3 receptor antagonists
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Employing a ligand-based approach, 3-methoxyquinoxalin-2-carboxamides were designed as serotonin type-3 (5-HT3) receptor antagonists and synthesized from the starting material o-phenylenediamine in a sequence of reactions. The structures of the
- Mahesh, Radhakrishnan,Devadoss, Thangaraj,Dhar, Arghya Kusum,Venkatesh, Sudali Muthu,Mundra, Sourabh,Pandey, Dilip Kumar,Bhatt, Shvetank,Jindal, Ankur Kumar
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p. 687 - 694
(2012/10/29)
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- Citric acid: An efficient and green catalyst for rapid one pot synthesis of quinoxaline derivatives at room temperature
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The condensation of o-phenylenediamines with 1,2-dicarbonyl compounds in the presence of citric acid afforded the corresponding quinoxaline derivatives in higher yields at room temperature in ethanol, and most of the reactions were completed in less than 1 min.
- Mahesh, Radhakrishnan,Dhar, Arghya Kusum,Sasank T.v.n.v., Tara,Thirunavukkarasu, Sappanimuthu,Devadoss, Thangaraj
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experimental part
p. 389 - 392
(2012/01/05)
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- Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: Design, synthesis and pharmacological evaluation of 3-ethoxyquinoxalin-2-carboxamides
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A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT3 receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3-ethoxyquin
- Mahesh, Radhakrishnan,Devadoss, Thangaraj,Pandey, Dilip Kumar,Bhatt, Shvetank
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scheme or table
p. 1253 - 1256
(2011/04/16)
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- New efficient access to fused (Het)Aryltetrahydroindolizinones via N-acyl iminium intermediates
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In this paper, we described the preparation of fused (Het)Aryltetrahydroindolizinones via N-acyl iminium intermediates. Two different routes were also explored to achieve the synthesis. The first one consists in the intramolecular reaction of β-hydroxylactams whereas the second route one is an intermolecular condensation between a 2-formylester or a β-alkoxylactone and an appropriate primary amine. We also developed two heterocyclic strategies to obtain the adequate unavailable starting materials in pyridine, pyrazine, quinoline, and quinaxoline series and then perform all inter or intramolecular reactions. Scope and limitations are given.
- Chiurato, Matteo,Boulahjar, Rajaa,Routier, Sylvain,Troin, Yves,Guillaumet, Gérald
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experimental part
p. 4647 - 4653
(2010/07/05)
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- Pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one: Synthesis and characterization of a novel tetracyclic ring system
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(Chemical Equation Presented) Derivatives of the hitherto unknown ring system, pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one, are synthesized in one step from the corresponding 1-substuituted or 1,3-disubstituted 2-pyrazolin-5-ones and 3-chloroquinoxaline-2-carbonyl chloride using calcium hydroxide in boiling 1,4-dioxane. The parent system carrying no substituent in positions 1 and 3 is obtained upon treatment of the 1-PMB (p-methoxybenzyl) protected congener with trifluoroacetic acid. Detailed NMR spectroscopic investigations including unambiguous chemical shift assignments of all 1H, 13C, and 15N resonances of the obtained tetracycles are reported.
- Eller, Gernot A.,Datterl, Barbara,Holzer, Wolfgang
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p. 1139 - 1143
(2008/04/12)
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- QUINOXALINES USEFUL AS INHIBITORS OF PROTEIN KINASES
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The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, c
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Page/Page column 43
(2008/06/13)
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- Amine compounds, their production and use
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The present invention provides a compound of the formula: wherein Ar represents an aromatic group which may be substituted; X represents methylene, S, SO, SO2or CO; Y represents a spacer having a main chain of 2 to 5 atoms; n represents an integer of 1 to 5; i) R1and R2each represents a hydrogen atom or a lower alkyl which may be substituted, ii) R1and R2form, taken together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted, or iii) R1or R2together with —(CH2)n—N═ form, bonded to a component atom of Ring B, a spiro-ring which may be substituted; Ring A represents an aromatic ring which may be substituted; Ring B represents a 4- to 7-membered nitrogen-containing non-aromatic ring which may be further substituted by alkyl or acyl, with a proviso that X represents S, SO, SO2or CO when Ring A has as a substituent a group represented by the formula: —NHCOR11 where R11represents alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group represented by the formula: —NHR12 where R12represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or a salt thereof; which has an excellent somatostatin receptor binding inhibition action.
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- Synthesis of substituted 2-ethoxycarbonyl- and 2-carboxyquinoxalin -3 ones for evaluation of antimicrobial and anticancer activity
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A series of variously substituted quinoxalin-3-ones bearing an ethoxycarbonyl or carboxy group in the C-2 position has been prepared and their structures proved by 1H NMR spectroscopy. The obtained compounds were investigated in vitro for antimicrobial and anticancer activities. Preliminary results showed a moderate activity against a few strains of bacteria but no significant anticancer and anti-HIV activity.
- Sanna, Paolo,Carta, Antonio,Loriga, Mario,Zanetti, Stefania,Sechi, Leonardo
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p. 455 - 461
(2007/10/03)
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- Synthesis and Chemistry of 3-Amino- and 3-Hydrazocarbonylquinoxalinone Derivatives
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3-Ethoxycarhonyl-2(1H)-quinoxalinone (1) reacts with nucleophiles, namely, dimethylamine, diethylamine, o- phenylenediamine and/or p-phenylenediamine to produce the corresponding 3-N-substituted-aminocarbonyl-2(1H)- quinoxalinones (3-6).Treatment of 1 with hydrazine hydrate produces the 2(1H)-quinoxalinone-3-carbohydrazide (2) with acylating reagents, namely, acetic anhydride, acetic acid or acetyl chloride/pyridine, phenylisothiocyanate, p-toluene-sulphonyl chloride and/or diethylmalonate to produce the corresponding 3-β-N-substituted-hydrazocarboxyl-2(1H)-quinoxalines (7-10, 12).Condensation of 2 with benzaldehyde, p-anisaldehyde, p-N-dimethylaminobenzaldehyde and/or p-nitrobenzaldehyde gives the corresponding 3-arylidenehydrazocarbonyl-2(1H)-quinoxalinones ( 11 a-d ).Treatment of 2 with acetylacetone gives 3-(3,5-dimethylpyrazol-1-yl-carbonyl)-2(1H)-quinoxaline ( 13).Diazodisation of 2 produces 2(1H)-guinoxalinone-3-carboazide (14) which when treated with absolute ethanol and/or t-butanol produces the corresponding 3-alkoxycarbonylaminuquinoxalinones (15, 16) and the both cyclise on treatment with hydrazine hydrate into triazinoquinoxaline (17).
- Badr, M. Z. A.,Mahgoub, S. A.,Atta, F. M.,Moustafa, O. S.,El-Latif, P. M. Abd
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p. 617 - 620
(2007/10/02)
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- Synthesis and reactions of 1-acetyl-1H-pyrazoloquinoxalines substituted at position-3
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3-Hydroxy, 3-chloro, 3-amino and 3-methoxy 1-acetyl-1H-pyrazoloquinoxalines have been prepared starting from diethyl malonate.Hydrolysis of these compounds under basic as well as acidic coditions has been studied and mechanisms have been discussed.The products have been separated using column chromatography and fully characterised by spectroscopic data (UV, IR, mass and PMR).
- Pillai, P. Madhavan,Bhat, V. Sanjeev
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p. 1024 - 1028
(2007/10/02)
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- Synthesis and Biological Activity of Heterocyclic Derivatives derived from Ethyl-2-hydroxyquinoxaline-3-carboxylate
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Ethyl-2-chloroquinoxaline-3-carboxylate obtained from ethyl-2-hydroxyquinoxaline-3-carboxylate upon treatment with morpholine gave ethyl-2-morpholinoquinoxaline-3-carboxylate (1).This ester upon reaction with hydrazine hydrate (99percent) gave respective carboxy hydrazide (2).This hydrazide on reaction with phenyl isothiocyanates gave thiosemicarbazides (3a-c).The thiosemicarbazides on reaction with concentrated sulphuric acid or anhydrous phosphoric acid gave 2-(4-substituted)-anilino-5-((2'-morpholino)quinoxalino)-1,3,4-thiadiazoles (4a-c).The thiosemicarbazides on reaction with 4percent sodium hydroxide formed 4-(para-substituted-phenyl)-3-mercapto-5-((2'-morpholino)quinoxalino)-1,2,4-triazoles (5a-c), and on reaction with I2 in KI gave 2-(4-substituted)anilino-5-((2'-morpholino)quinoxalino)-1,3,4-oxadiazoles (6a-c) respectively.
- Fernandes, P. S.,Sonar, T. M.
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p. 427 - 429
(2007/10/02)
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