- Specificity and mechanism of acinetobacter baumanii nicotinamidase: Implications for activation of the front-line tuberculosis drug pyrazinamide
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TB or not TB active: The high-resolution crystal structures (see picture) of the zinccontaining metalloenzyme nicotinamidase in complex with nicotinic acid and pyrazinoic acid reveal new aspects of enzyme mechanism that help to explain the activation of a
- Fyfe, Paul K.,Rao, Vincenzo A.,Zemla, Aleksandra,Cameron, Scott,Hunter, William N.
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- Synthesis and spectroscopic study of three new oxadiazole derivatives with detailed computational evaluation of their reactivity and pharmaceutical potential
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Local reactivity properties and potential for application in new pharmaceutical compounds have been addressed for the three newly synthetized oxadiazole derivatives (2-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (ORTHONITRO), 2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (METANITRO) and 2-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (PARANITRO), by application of computational molecular modeling. Within the framework of density functional theory (DFT) this study encompassed calculations of molecular electrostatic potential (MEP), average local ionization energies (ALIE) and bond dissociation energies for hydrogen abstraction (H-BDE). MD simulations have been used in order to assess the influence of water and to identify the atoms of these molecules with preference towards the interaction with water molecules. Molecular docking procedure has been applied in order to check the binding activity of these derivatives against the Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor proteins. The pharmaceutical potential of these derivatives has been assessed by the calculations of the well-established drug likeness parameters. A strong out-of-plane CH mode of the phenyl rings are observed at 769 cm?1 for ORTHONITRO, 768 cm?1 for METANITRO and at 848 cm?1 for PARANITRO in the IR spectrum as expected for substituted benzenes. The VCD signals, corresponding to C[dbnd]N and NO2 modes of the title compounds are good markers for assigning of absolute configuration. In the title compounds, in ORTHONITRO, the oxadiazole ring is tilted from the phenyl and pyrazine ring while for METANITRO and PARANITRO, there is a planar orientation. The first hyperpolariazabilities of ORTHONITRO, METANITRO and PARANITRO are respectively, 34.83, 54.50 and 174.05 times that of urea. For all the compounds, HOMO is delocalized over the pyrazine and oxadiazole rings, while LUMO is delocalized over whole molecule, except pyrazine ring of ORTHONITRO, over phenyl ring and NO2 group of METANITRO and in the entire molecule of PARANITRO. The title compounds are docked with the proteins, Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor and METANITRO exhibits more inhibitory activity against the receptors than the other ligands. The results obtained from anti-TB activity are more promising as the compounds were found to be more potent than reference standard, ORTHONITRO (MIC = 1.6 μg/ml), METANITRO (MIC = 0.8 μg/ml), PARANITRO (MIC = 1.6 μg/ml), streptomycin (MIC = 6.2 μg/ml) and pyrazinamide (MIC = 3.1 μg/ml).
- Mary, Y. Sheena,Miniyar, Pankaj B.,Mary, Y. Shyma,Resmi,Panicker, C. Yohannan,Armakovi?, Stevan,Armakovi?, Sanja J.,Thomas, Renjith,Sureshkumar
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- Hederagenin compound H-X with anti-lung cancer effect and preparation method and application thereof
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The invention provides a hederagenin compound H-X with an anti-tumor effect and a preparation method and application thereof. The structural general formula 1 is shown in the specifications. Most of the derivatives provided by the invention have obvious inhibition effects on tumor cells A549, MCF-7 and HepG2, and the compound hederagenin-2, 6-dimethylpyrazine (H-08) shows good selectivity betweentumors and normal conditions, especially on lung cancer A549 cells. The IC50 of the compound to A549, MCF-7, HepG2, MDCK and H9c2 is 3.45+/-0.59 muM, 8.73+/-1.49 muM, 8.71+/-0.38 muM, 14.11+/-0.04 muM, and 16.69+/-0.12 muM, the inhibition effect on A549 cells is similar to that of a positive drug cis-platinum (IC50 is 3.85+/-0.63 muM), but the toxicity on MDCK and H9c2 is obviously lower than thatof cis-platinum.
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Paragraph 0048; 0049; 0051; 0052; 0120; 0121
(2020/04/17)
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- Novel pyrazine based anti-tubercular agents: Design, synthesis, biological evaluation and in silico studies
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TB continues to be a leading health threat despite the availability of powerful anti-TB drugs. We report herein the design and synthesis of various hybrid molecules comprising pyrazine scaffold and various formerly identified anti-mycobacterial moieties. Thirty-one compounds were screened in vitro for their activity against Mycobacterium tuberculosis H37Rv strain using MABA assay. The results revealed that six compounds (8a, 8b, 8c, 8d, 14b and 18) displayed significant activity against Mtb with MIC values ≤6.25 μg/ml versus 6.25 μg/ml for pyrazinamide. The most active compounds were then assessed for their in vitro cytotoxicity against PBMC normal cell line using MTT assay and showed SI > 200. Several in silico studies have been carried out for target fishing of the novel compounds such as shape-based similarity, pharmacophore mapping and inverse docking. Based on this multi-step target fishing study, we suggest that pantothenate synthetase could be the possible target responsible for the action of these compounds. The most active compounds were then successfully docked into the active site of pantothenate synthetase enzyme with favorable binding interactions. In addition, in silico prediction of physicochemical, ADMET and drug-like properties were also determined indicating that compounds 8b, 8c and 8d are promising candidates for the development of new anti-TB agents with enhanced activity and better safety profile.
- Abdel-Aziz, Marwa M.,Abdel-Ghany, Yasser S.,El-Hawash, Soad A.,Elzahhar, Perihan A.,Hassan, Nayera W.,Ismail, Azza,Nassra, Rasha,Saudi, Manal N.,Sriram, Dharmarajan
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- Design, synthesis, and cytotoxic analysis of novel hederagenin–pyrazine derivatives based on partial least squares discriminant analysis
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Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He–pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 μM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure–activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.
- Fang, Kang,Zhang, Xiao-Hua,Han, Yao-Tian,Wu, Gao-Rong,Cai, De-Sheng,Xue, Nan-Nan,Guo, Wen-Bo,Yang, Yu-Qin,Chen, Meng,Zhang, Xin-Yu,Wang, Hui,Ma, Tao,Wang, Peng-Long,Lei, Hai-Min
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- Carboxylic acid complex and synthesis method thereof
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The invention discloses a carboxylic acid complex, belonging to the technical field of chemical synthesis. The carboxylic acid complex is composed of 30-50ml of anhydrous ethanol, 0.2-0.5 mol/L 2-methyl pyrazine, 1.25-1.6 mol/L potassium hydroxide solution and 5.0*10-5.0*10 mol/L catalyst. The synthesis method of the carboxylic acid complex comprises the following steps: S1: adding the 5.0*10-5.0*10 mol/L catalyst to react; S2: after the reaction finishes, carrying out vacuum filtration while the solution is hot; and S3: filtering the precipitate generated in the step S2, washing, and recrystallizing with hot water to obtain the solid carboxylic acid complex. The operating method is simple, and the carboxylic acid complex has high yield. The added catalyst converts oxygen molecules into an effective oxidizer, and thus, substitutes the expensive and polluting chemical oxidizer, thereby lowering the production cost, reducing the generation of three wastes and conforming to the energy-saving demand of clean production at present.
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Paragraph 0029; 0030; 0039; 0040; 0049; 0050
(2017/07/20)
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- Biotransformation of aromatic and heterocyclic amides by amidase of whole cells of Rhodococcus sp. MTB5: Biocatalytic characterization and substrate specificity
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In this study, an amidohydrolase activity of amidase in whole cells of Rhodococcus sp. MTB5 has been used for the biotransformation of aromatic, monoheterocyclic and diheterocyclic amides to corresponding carboxylic acids. Benzoic acid, nicotinic acid and pyrazinoic acid are carboxylic acids which have wide industrial applications. The amidase of this strain is found to be inducible in nature. The biocatalytic conditions for amidase present in the whole cells of MTB5 were optimized against benzamide. The enzyme exhibited optimum activity in 50 mM potassium phosphate buffer pH 7.0. The optimum temperature and substrate concentrations for this enzyme were 50 °C and 50 mM, respectively. The enzyme was quite stable for more than 6 h at 30 °C. It showed substrate specificity against different amides, including aliphatic, aromatic and heterocyclic amides. Under optimized reaction conditions, the amidase is capable of converting 50 mM each of benzamide, nicotinamide and pyrazinamide to corresponding acids within 100, 160 and 120 min, respectively, using 5 mg dry cell mass (DCM) per mL of reaction mixture. The respective percent conversion of these amides was 95.02%, 98.00% and 98.44% achieved by whole cells. The amidase in whole cells can withstand as high as 383 mM concentration of product in a reaction mixture and above which it undergoes product feedback inhibition. The results of this study suggest that Rhodococcus sp. MTB5 amidase has the potential for large-scale production of carboxylic acids of industrial value.
- Ismailsab, Mukram,Monisha,Reddy, Pooja V.,Santoshkumar,Nayak, Anand S.,Karegoudar, Timmanagouda B.
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- Kinetics and mechanistic study of permanganatic oxidation of pyrazinamide in acidic media
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The oxidation of pyrazinamide by potassium permanganate in acidic media was studied spectrophotometrically at 525 nm. It was found to be zero order with respect to oxidant, fractional order with respect to hydrogen ion concentration and first order with respect to substrate. The average (ΔG#) was found to be 87.60 kJ mol-1. The values ΔS# was found to be -0.2132 kJ mol-1 and energy of activation was found to be 23.95 kJ mol-1. A suitable mechanism is proposed based on the experimental conditions.
- Gour, Sandipsingh,Hussain, Sayyed,Farooqui, Mazahar
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p. 181 - 185
(2013/06/04)
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- Facile, one-step production of niacin (vitamin B3) and other nitrogen-containing pharmaceutical chemicals with a single-site heterogeneous catalyst
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Niacin (3-picolinic acid), which is extensively used as vitamin B 3 in foodstuffs and as a cholesterol-lowering agent, along with other oxygenated products of the picolines, 4-methylquinoline, and a variety of pyrimidines and pyridazines, may be produced in a single-step, environmentally benign fashion by combining single-site, open-structure, heterogeneous catalysts witha solid source of active oxygen, namely acetyl peroxyborate (APB), in the absence of an organic solvent. The high activities, selectivities, and the relatively mild conditions employed with this single-site heterogeneous catalyst, coupled with ease of transport, storage, and stability of the solid oxidant, augurs well for the future use of APB in conjunction with other open-structure, single-site catalysts for fine-chemical, pharmaceutical, and agrochemical applications.
- Raja, Robert,Thomas, John Meurig,Greenhill-Hooper, Michael,Ley, Steven V.,Almeida Paz, Filipe A.
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experimental part
p. 2340 - 2348
(2009/04/11)
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- Experimental thermochemical study of three monosubstituted pyrazines
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The standard (p° = 0.1 MPa) molar enthalpies of formation of liquid pyrazinecarbonitrile and of crystalline pyrazinecarboxylic acid and pyrazinamide were measured, at T= 298.15 K, by static bomb calorimetry and the standard molar enthalpies of vaporization or of sublimation, at T= 298.15 K, were obtained using Calvet microcalorimetry. These values were used to derive the respective standard molar enthalpies of formation in gaseous phase.
- Ribeiro Da Silva, Maria D. M. C.,Miranda, Margarida S.,Vaz, Claudia M. V.,Matos, M. Agostinha R.,Acree Jr.
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- Microwave Assisted Improved Synthesis of 6-Formylpterin and Other Heterocyclic Mono- and Di-aldehydes
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2-Pivaloylamino-6-formylpterin (1a) and a series of other important heterocyclic aldehydes (2a, 3a, 4a, 6a, and 7a) have been synthesized in good yield by microwave assisted selenium dioxide oxidation. Interestingly, 2-methylpyrazine gives 2-pyrazinecarboxylic acid (5a) under the similar condition.
- Goswami, Shyamaprosad,Adak, Avijit Kumar
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p. 475 - 480
(2007/10/03)
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- Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents
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A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Young, Jonathan R.,Huang, Song X.,Chen, Irene,Walsh, Thomas F.,DeVita, Robert J.,Wyvratt Jr., Matthew J.,Goulet, Mark T.,Ren, Ning,Lo, Jane,Yang, Yi Tien,Yudkovitz, Joel B.,Cheng, Kang,Smith, Roy G.
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p. 1723 - 1727
(2007/10/03)
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- Kinetics of the highly selective liquid-phase oxidation of side chain alkyl groups in 2-methylpyrazine and picolines by selenium dioxide
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Kinetics of the liquid-phase oxidation of alkyl groups in 2-methylpyrazine and picolines with selenium dioxide at moderate conditions were studied. Thus, 2-methylpyrazine was oxidized to pyrazinoic acid with selenium dioxide in pyridine at 115 °C with 99% selectivity at a 2-methylpyrazine conversion of 100% in 8 h. It was deduced that the reaction follows secondorder kinetics and the activation energy was found to be 35 kcal/mol. The same reaction-scheme was found to hold for picolines oxidation to obtain picolinic acids. The byproduct selenium, formed in the reaction, was converted back to selenium dioxide by nitric acid oxidation with 100% selectivity.
- Mukhopadhyay, Sudip,Chandalia, Sampatraj B.
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p. 455 - 459
(2013/09/08)
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- Kinetics of catalyzed liquid-phase oxidation of p-nitrotoluene by air in basic medium
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An alternative method for the oxidation of nitrotoluenes is described, using air with a cobalt catalyst in basic medium. Different process parameters were studied to realize the true kinetics of the process. At 28 °C and 16 atm air pressure, 96% selectivity at a conversion level of 40% forp-nitrotoluene was achieved in 18 h using cobalt phthalocyanine. For a given initial concentration of p-nitrotoluene, the reaction was found to be of first-order kinetics.
- Chandalia,Mukhopadhyay
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p. 109 - 113
(2013/09/08)
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- ANODIC OXIDATION OF METHYL-SUBSTITUTED NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS AT THE ACTIVATED NICKEL OXIDE ELECTRODE
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Methyl derivatives of several nitrogen-containing heterocyclic compounds were converted into the corresponding carboxylic acids by means of electrochemical oxidation at the nickel oxohydroxide anode in alkaline medium, using a nondiaphragm electrolyzer.The oxidation of 2,5-dimethylpyrazine was used to demonstrate the effect of adding chromium (III) and cobalt (II) compounds to the reaction mixture.The composition and electronic state of the anode surface were studied using x-ray diffraction and XPS methods.
- Feldman, D.,Chervenka, M.,Stokh, E.,Shimanska, M.,Khaber, E.
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- NEW METHOD FOR OBTAINING PYRAZINECARBOXYLIC ACID
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The generation of a carbanion from 2-methylpyrazine by phase-transfer catalysis and its autooxidation to pyrazinecarboxylic acid have been studied.This acid is the starting material for the effective antitubercular agent pyrazinamide.Optimum conditions were found for the synthesis of pyrazinecarboxylic acid.Molecular oxygen, the cheapest and most ecological agent, was used as oxidizing agent.
- Iovel', I. G.,Shimanskaya, M. V.
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p. 1696 - 1699
(2007/10/02)
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- AUTOOXIDATION OF METHYLHETEROCYCLES UNDER PHASE TRANSFER CATALYSIS CONDITIONS
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The autooxidation of methyl- and dimethyl-substituted N-, S-, and O-heterocyclic compound derivatives has been studied in 1,2-dimethoxyethane-t-BuOK in the presence of 18-crown-6.Mono- and dicarboxylic acid derivatives of pyrazine, pyridine, pyrimidine, and thiophene have been synthesized.
- Iovel', I. G.,Gol'dberg, Yu. Sh.,Gaukhman, A. P.,Zolotoyabko, R. M.,Shimanskaya, M. V.
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p. 768 - 771
(2007/10/02)
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- Process for the preparation of 7-amino and 7-substituted amino-desacetoxycephalosporins
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An improved process is disclosed for the preparation of 7-amino and 7-substituted amino-desacetoxycephalosporins in which the corresponding 6-substituted amino penicillin sulphoxide is heated in the presence of an acidic substance which causes expansion of the penam ring in the reactant to the Δ3 cephem ring in the product in the presence of a silicon containing compound. The process comprises adding sulphamide or a silylsulphamide or a silylsulphamoyl to the reaction or utilizing a silylsulphamide or silylsulphamoyl as the silicon containing compound.
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- Synthesis of Pyrazinamide
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The key intermediate, pyrazinoic acid (III) in the synthesis of pyrazinamide has been prepared starting from 2,3-dibromsuccinic acid.
- Rao, A. V. Rama,Yadav, J. S.,Ravichandran, K.,Sahasrabudhe, A. B.,Chaurassia, S. S.
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- Structural and Solvent Effects on Alkaline Hydrolysis of Heterocyclic Esters
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Alkaline hydrolysis of the three isomeric ethyl pyridine-carboxylates (I-III), ethyl pyridine-2-acetate (IV), ethyl pyridine-3-acetate (V), ethyl pyrazine-carboxylate (VI), ethyl furan-2-carboxylate (VII) and ethyl thiophen-2-carboxylate (VIII), have been investigated in ethanol-water and DMSO-water media.The structural effects on the hydrolysis of I-III have been discussed in terms of aza sigma values.The studies clearly show that the assumption of treating ring nitrogen as a ring substituent is truly valid.Structural effects vis-a-vis solvent effects on the hydrolysis of IV and V are discussed in detail.Application of Laidler-Landskroener equation to the alkaline hydrolysis of these esters in aq. ethanol is found to give normal values for the radius of the transition state.
- Venkoba Rao, G.,Balakrishnan, M.,Venkatasubramanian, N.,Subramanian, P. V.,Subramanian, V.
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p. 793 - 795
(2007/10/02)
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