- FT-IR and FT-Raman characterization and investigation of reactive properties of N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide by molecular dynamics simulations and DFT calculations
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The FT-IR and FT-Raman spectra of N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide were recorded and the experimentally observed wavenumbers are compared with the theoretically obtained wavenumbers. The redshift of the N[sbnd]H stretching mode in the IR spectrum from the computed value indicated the weakening of the N[sbnd]H bond. The ring breathing modes of the phenyl ring and pyrazine ring are assigned at 819 and 952?cm?1 theoretically. Using natural bond orbital analysis, the stability of the molecule arising from hyperconjugative interaction and charge delocalization has been analyzed. The most reactive sites in the molecule were identified by molecular electrostatic potential map. The calculations of the average local ionization energy (ALIE) were used for visualization and determination of molecule sites possibly prone to electrophilic attacks. Further information on possible reactive centers of title molecule has been obtained by calculations of Fukui functions. Vulnerability of title molecule towards autoxidation mechanism was investigated by calculations of bond dissociation energies (BDE), while vulnerability towards hydrolysis was investigated by calculations of radial distribution functions (RDF) as obtained after molecular dynamics (MD) simulations. Molecular docking studies suggest that the compound might exhibit inhibitory activity against mGluRs.
- Ranjith,Al-Abdullah, Ebtehal S.,Al-Omary, Fatmah A.M.,El-Emam, Ali A.,Anto,Sheena, Mary Y.,Armakovi?, Stevan,Armakovi?, Sanja J.,Zitko, Jan,Dolezal, Martin,Van Alsenoy
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- Pyrazine-imide complexes: Reversible redox and MOF building blocks
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The synthesis of the symmetric pyrazine imide ligand, N-(2-pyrazylcarbonyl)-2-pyrazinecarboxamide, (Hdpzca) and five new first row transition metal complexes of it are reported: [MII(dpzca)2], MII = Fe, Cu, Zn; [CuII(dpzca)(H2O)2]BF4, [CuII(dpzca)(H2O)3]2SiF6. The crystal structures of Hdpzca, [CoII(dpzca)2], [CuII(dpzca)2], {[CoIII(dpzca)2](BF4)}2·5CH3CN and [CuII(dpzca)(H2O)3]2SiF6·2H2O were determined and reveal an orthogonal positioning of the 'spare' pyrazine nitrogen atoms and 'spare' pairs of imide oxygen atoms. The [MII(dpzca)2] complexes are therefore useful six-coordinate building blocks for producing larger supramolecular assemblies. Two examples of secondary assembly of [MII(dpzca)2] complexes, with M = Co and Ni, with silver nitrate gave single crystals; {[CoIII(dpzca)2Ag](NO3)2·2H2O}n and {([NiII(dpzca)2AgI1/2](1/2NO3)(xH2O}n were structurally characterised. The redox processes of [MII(dpzca)2], with MII = Fe, Ni, Cu and Zn, are reported and, as seen for MII = Co, reversible metal- and ligand-based redox processes are observed, with Em(MII/MIII) values 0.15-0.24 V higher than for the analogous complexes of Hpypzca (non-symmetric pyridine/pyrazine imide ligand), and 0.35-0.36 V higher than for the complexes of Hbpca (symmetric pyridine imide ligand). This journal is
- Cowan, Matthew G.,Miller, Reece G.,Brooker, Sally
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- Organosilatranes with Acylthiourea Derivatives – Metal-Ion Binding, Substituent-Dependent Sensitivity, and Prospects for the Fabrication of Magnetic Hybrids
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A variety of topologically interesting acylthiourea-tethered organosilatranes (AcTu-OS) were prepared, and their function as metal-ion binding sites was investigated. The prepared compounds have been characterized by elemental analysis; FTIR, UV/Vis and NMR (1H and13C) spectroscopy; and mass spectrometry. The organosilicon complexes 4a–4e possess diverse coordination abilities for the surveyed metal ions (Cu2+, Cd2+, Hg2+and Pb2+), as was appraised by the corresponding absorption shifts in the UV/Vis spectra. In addition, a facile preparatory route for the covalent grafting of the most efficient receptor 4e onto a silica-encrusted magnetic nanosupport was implemented. The resultant organic–inorganic hybrid nanoparticles (H-NPs) were characterized by physicochemical techniques such as FTIR spectroscopy, XRD, thermogravimetric analysis (TGA), TEM, field-emission SEM (FE-SEM) and energy-dispersive X-ray spectroscopy (EDX). The grafting of the sensory module afforded active sites for the adsorption of metal ions from the aqueous solution which is outlined using the Langmuir adsorption isotherm. The potential in sensing, sorbent properties and facile magnetic recovery of the hybrid evinces the separation process practical to undertake environmental issues.
- Singh, Gurjaspreet,Rani, Sunita
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- Self-assembled nanoparticles as multifunctional drugs for anti-microbial therapies
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A self-assembled nanoparticle containing a photosensitizer and a Trojan-horse moiety (cholesterol), binds an anti-TB pro-drug and increases 1000-fold its activity against mycobacteria. These minimalist constructs will allow development of economically viable, efficient drug preparations for the treatment of drug-resistant TB infections.
- Bhatti, Manpreet,McHugh, Timothy D.,Milanesi, Lilia,Tomas, Salvador
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- Design and Discovery of Novel Antifungal Quinoline Derivatives with Acylhydrazide as a Promising Pharmacophore
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Inspired by natural 2-quinolinecarboxylic acid derivatives, a series of quinoline compounds containing acylhydrazine, acylhydrazone, sulfonylhydrazine, oxadiazole, thiadiazole, or triazole moieties were synthesized and evaluated for their fungicidal activity. Most of these compounds exhibited excellent fungicidal activity in vitro. Significantly, compound 2e displayed the superior in vitro antifungal activity against Sclerotinia sclerotiorum, Rhizoctonia solani, Botrytis cinerea, and Fusarium graminearum with the EC50 values of 0.39, 0.46, 0.19, and 0.18 μg/mL, respectively, and were more potent than those of carbendazim (EC50, 0.68, 0.14, >100, and 0.65 μg/mL, respectively). Moreover, compound 2e could inhibit spore germination of F. graminearum. Preliminary mechanistic studies showed that compound 2e could cause abnormal morphology of cell walls and vacuoles, loss of mitochondrion, increases in membrane permeability, and release of cellular contents. These results indicate that compound 2e displayed superior fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.
- Yang, Yu-Dong,He, Ying-Hui,Ma, Kun-Yuan,Li, Hu,Zhang, Zhi-Jun,Sun, Yu,Wang, Yu-Ling,Hu, Guan-Fang,Wang, Ren-Xuan,Liu, Ying-Qian
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p. 8347 - 8357
(2021/08/16)
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- Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation
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Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3′-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC50 = 0.018 μM) exhibits 17.2-fold improved potency than the initial compound 1 (IC50 = 0.31 μM). Its potency is comparable to that of topiroxostat (IC50 = 0.013 μM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors.
- Zhang, Ting-jian,Tu, Shun,Zhang, Xu,Wang, Qiu-yin,Hu, Sen-sen,Zhang, Yi,Zhang, Zhen-hao,Wang, Zhao-ran,Meng, Fan-hao
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- Synthesis of N-trifluoromethyl amides from carboxylic acids
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Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
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supporting information
p. 2245 - 2255
(2021/08/12)
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- The bioisosteric modification of pyrazinamide derivatives led to potent antitubercular agents: Synthesis via click approach and molecular docking of pyrazine-1,2,3-triazoles
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Tuberculosis remains as a major public health risk which causes the highest mortality rate globally and an improved regimen is required to treat the drug-resistant strains. Pyrazinamide is a first-line antitubercular drug used in combination therapy with other anti-TB drugs. Herein, we describe the modification of pyrazinamide structure using bioisosterism and rational approaches by incorporating the 1,2,3-triazole moiety. Three sets of pyrazine-1,2,3-triazoles (3a-o, 5a-o and 9a-l) are designed, synthesized and evaluated for their in vitro inhibitory potency against mycobacterium tuberculosis H37Rv. The pyrazine-1,2,3-triazoles synthesized through the bioisosteric modification displayed improved activity as compared to rationally modified pyrazine-1,2,3-triazoles. Among 42 title compounds, seven derivatives demonstrated significant anti-tubercular activity with the MIC of 1.56 μg/mL, which are two-fold more potent than the parent compound pyrazinamide. Further, the synthesized pyrazinamide analogs demonstrated moderate inhibition activity against several bacterial strains and possessed an acceptable in vitro cytotoxicity profile as well. Additionally, the activity profile of pyrazine-1,2,3-triazoles was validated by performing the molecular docking studies against the Inh A enzyme. Furthermore, in silico ADME prediction revealed good oral bioavailability for the potent molecules.
- Reddyrajula, Rajkumar,Dalimba, Udayakumar
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supporting information
(2019/12/24)
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- 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers
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Aiming to deepen the structure–activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.
- Bartolucci, Gianluca,Braconi, Laura,Colabufo, Nicola Antonio,Contino, Marialessandra,Dei, Silvia,Giampietro, Roberta,Manetti, Dina,Perrone, Maria Grazia,Riganti, Chiara,Romanelli, Maria Novella,Teodori, Elisabetta,Chiaramonte, Niccolò
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p. 974 - 992
(2020/04/24)
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- Recognition of Al3+ through the off-on mechanism as a proficient driving force for the hydrolysis of BODIPY conjugated Schiff base and its application in bio-imaging
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Two new BODIPY azine bearing quinoline and pyrazine attached Schiff base chemosensors (R1 and R2) have been synthesized and applied for the detection of Al3+ in CH3CN/H2O medium. Intramolecular hydrogen bonding makes both the sensors rigid and helps to encapsulate Al3+ in the cavity. The pink colour of R1 and R2 has been changed to green fluorescent upon excess addition of Al3+ which is only because of the hydrolysis of imine bond to regenerate compound 8. Another nitrogen atom present in quinoline and in pyrazine moiety made R1 and R2 more efficient in sensing of Al3+ ion compare to R1D, R2B and R2D. Cell viability and fluorescence microscopic experiments showed that the chemosensors are cytocompatible and can be used as an effective fluorescent probe for detecting Al3+ ion in the living cell.
- Kashyap, Kumari Somlata,Kumar, Ashish,Hira, Sumit Kumar,Dey, Swapan
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- Design, synthesis, characterization and antitubercular activity of some novel 2, 4-disubstituted thiazole derivatives
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Literature reviews reveal that thiazole and pyrazine carboxamide derivatives exhibit anticonvulsant, antimicrobial, anticancer and anti-tubercular activities due to the presence of –S-C=N- and-CO–NH- moiety. A series of thiazolyl pyrazine carboxamide derivatives (5a-j) were synthesized by condensation reaction between 2-amino, 4-substituted phenyl 2-amino thiazole and pyrazine 2-carboxylic acid. These synthesized thiazole derivatives (5a-j) were evaluated for their inhibitory activity against Mycobacterium tuberculosis (Mtb), H37Rv using microplate Alamar Blue assay (MABA). The compound, 5c and 5h showed high anti-mycobacterial activity with MIC value of 6.25 μg/ml, and the compound 5g also exhibited anti-mycobacterial activity with MIC value of 12.50 μg/ml. Molecular docking studies of these synthesized molecules with b-Ketoacyl-ACP Synthase (KasA) protein of Mycobacterium tuberculosis (Mtb) have been carried out to understand the mechanism of antimycobacterial action.
- Gobala Krishnan,Gnanaprakash,Chandrasekhar
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p. 1504 - 1509
(2019/08/12)
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- An expedient ‘click’ approach for the synthetic evaluation of ester-triazole-tethered organosilica conjugates
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The present work articulates the synthesis of a new series of organo-functionalized triethoxysilanes derived from versatile carboxylic acids and 3-azidopropyltriethoxysilane in excellent yields. A proficient and convenient route implicating the Cu(I)-catalysed 1,3-cycloaddition of organic azide with terminal alkynes, labelled as click silylation, has been developed for the generation of ester-triazole-linked alkoxysilanyl scaffolds (4a–f). All the synthesized compounds have been thoroughly characterized using elemental analysis and Fourier transform infrared, 1H NMR and 13C NMR spectroscopic techniques. Importantly, the fabricated alkoxysilanes are potentially amenable for an in situ sol–gel condensation reaction with silica nanospheres leading to the incorporation of organic functionality via covalent grafting onto the nanostructured particle system. As a proof of concept, a one-pot preparation of organic–inorganic hybrid nanoparticles is presented using bis-silane 4?f. The efficiency and selectivity of the prepared nanocomposite towards metal ions is highlighted using adsorption experiments, and the immobilized nanoparticles present a high sensing efficiency towards Cu2+ and Pb2+ ions while demonstrating better response than that of the bulk material.
- Singh, Gurjaspreet,Rani, Sunita
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- Design, synthesis and antimycobacterial activity of hybrid molecules combining pyrazinamide with a 4-phenylthiazol-2-amine scaffold
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Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for in vitro growth inhibition activity against M. tuberculosis H37Rv, M. kansasii, M. avium and M. smegmatis by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for in vitro cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro-N-[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited M. tuberculosis, M. kansasii, and M. avium with MIC = 0.78 μg mL-1 (2.3 μM) and a selectivity index related to HepG2 cells of SI > 20. Structure-activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.
- Zitko, Jan,Jand'Ourek, Ond?ej,Paterová, Pavla,Navrátilová, Lucie,Kune?, Ji?í,Vin?ová, Jarmila,Dole?al, Martin
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p. 685 - 696
(2018/05/03)
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- Copper-Catalyzed Electrochemical C-H Amination of Arenes with Secondary Amines
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Electrochemical oxidation represents an environmentally friendly solution to conventional methods that require caustic stoichiometric chemical oxidants. However, C-H functionalizations merging transition-metal catalysis and electrochemical techniques are, to date, largely confined to the use of precious metals and divided cells. Herein, we report the first examples of copper-catalyzed electrochemical C-H aminations of arenes at room temperature using undivided electrochemical cells, thereby providing a practical solution for the construction of arylamines. The use of n-Bu4NI as a redox mediator is crucial for this transformation. On the basis of mechanistic studies including kinetic profiles, isotope effects, cyclic voltammetric analyses, and radical inhibition experiments, the reaction appears to proceed via a single-electron-transfer (SET) process, and a high valent Cu(III) species is likely involved. These findings provide a new avenue for transition-metal-catalyzed electrochemical C-H functionalization reactions using redox mediators.
- Yang, Qi-Liang,Wang, Xiang-Yang,Lu, Jia-Yan,Zhang, Li-Pu,Fang, Ping,Mei, Tian-Sheng
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supporting information
p. 11487 - 11494
(2018/09/13)
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- The therapeutic compound, use and related method (by machine translation)
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PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a compound or its salt which prevents or treats a central nervous system disease in which integration dysfunction syndrome and agnosia are enumerated as exemplary disorders.SOLUTION: The pharmaceutical composition includes the compound or its salt represented by chemical formula (A) which modulates striatal-enriched protein tyrosine phosphatase (STEP).
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Paragraph 01359; 1360
(2017/06/29)
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- Pd(II)-Catalyzed, Picolinamide-Assisted, Z-Selective γ-Arylation of Allylamines to Construct Z-Cinnamylamines
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Investigations of Pd(II)-catalyzed, picolinamide-assisted, γ-C(sp2)-H activation and Z-selective arylation of allylamines are reported. The reactions of N-allylpicolinamides with various aryl iodides in the presence of the catalyst Pd(OAc)2 and additive AgOAc have led to the selective γ-arylation of allylamines to construct various cinnamylamines with moderate to good yields and good to high E/Z ratios. To obtain good E/Z ratios, the Pd(II)-catalyzed arylation reaction of N-allylpicolinamides was probed using different additives, directing groups, and reaction conditions. The Pd(II)-catalyzed arylation of an allylamine containing both γ-C(sp2)-H and γ-C(sp3)-H bonds afforded moderate yields of the γ-C(sp2)-H and γ-C(sp3)-H bisarylated cinnamylamines. Although Heck-type γ-arylations of allylamines have generally afforded the E-cinnamylamines, the bidentate directing group picolinamide-directed arylations of allylamines were found to be Z-selective. A plausible mechanism was proposed for the observed regioselectivity and Z-selective arylation of N-allylpicolinamides. Additionally, the Pd(II)-catalyzed arylation of an N-allyl-5-methylisoxazole-3-carboxamide afforded the E-cinnamylamines plausibly via a ligand-free Heck-type reaction mechanism.
- Parella, Ramarao,Babu, Srinivasarao Arulananda
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p. 6550 - 6567
(2017/07/15)
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- Novel methylselenoesters as antiproliferative agents
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Selenium (Se) compounds are potential therapeutic agents in cancer. Importantly, the biological effects of Se compounds are exerted by their metabolites, with methylselenol (CH3SeH) being one of the key executors. In this study, we developed a new series of methylselenoesters with different scaffolds aiming to modulate the release of CH3SeH. The fifteen compounds follow Lipinski’s Rule of Five and with exception of compounds 1 and 14, present better drug-likeness values than the positive control methylseleninic acid. The compounds were evaluated to determine their radical scavenging activity. Compound 11 reduced both DPPH and ABTS radicals. The cytotoxicity of the compounds was evaluated in a panel of five cancer cell lines (prostate, colon and lung carcinoma, mammary adenocarcinoma and chronic myelogenous leukemia) and two non-malignant (lung and mammary epithelial) cell lines. Ten compounds had GI50 values below 10 μM at 72 h in four cancer cell lines. Compounds 5 and 15 were chosen for further characterization of their mechanism of action in the mammary adenocarcinoma cell line due to their similarity with methylseleninic acid. Both compounds induced G2/M arrest whereas cell death was partially executed by caspases. The reduction and metabolism were also investigated, and both compounds were shown to be substrates for redox active enzyme thioredoxin reductase.
- Díaz-Argelich, Nuria,Encío, Ignacio,Plano, Daniel,Fernandes, Aristi P.,Palop, Juan Antonio,Sanmartín, Carmen
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- Design, synthesis and biological activity of pyrazinamide derivatives for anti-Mycobacterium tuberculosis
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A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by 1H NMR, 13C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0 μg/mL.
- Zhou, Shiyang,Yang, Shanbin,Huang, Gangliang
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p. 1183 - 1186
(2017/11/22)
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- Design, synthesis and anti-mycobacterial evaluation of some new N-phenylpyrazine-2-carboxamides
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N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH3-POA, 6-Cl-POA, 5-tert-butyl-POA and 5-tert-butyl-6-Cl-POA were designed and synthesised. The phenyl part was substituted with simple hydrophobic substituents chosen from methyl and halogens. 5-tert-Butyl-N-(5-fluoro-2-methylphenyl)pyrazine-2-carboxamide (9), N-(3-chloro-4-methylphenyl)-5-methylpyrazine-2-carboxamide (12), 6-chloro-N-(3-chloro-4-methylphenyl)pyrazine-2-carboxamide (13) and 6-chloro-N-(5-iodo-2-methylphenyl)pyrazine-2-carboxamide (18) possessed whole cell anti-mycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) of around 10 μM. Importantly, no cytotoxicity in the HepG2 model was detected in vitro at the concentrations tested and the estimated IC50 values were in hundreds of μM, indicating promising selectivity. N-(3-Chloro-4-methylphenyl)pyrazine-2-carboxamide (11) and N-(4-chloro-2-iodophenyl)pyrazine-2-carboxamide (21) exerted significant activity against Mycobacterium kansasii with MIC 12.6 μM and 8.7 μM, respectively. No activity was detected against Mycobacterium avium. SAR were in accordance with those observed for the derivatives previously published.
- Zitko, Jan,Barbora, Servusova-Vanaskova,Paterova, Pavla,Navratilova, Lucie,Trejtnar, Frantisek,Kunes, Jiri,Dolezal, Martin
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p. 649 - 657
(2016/03/05)
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- Proteasome inhibitor delanzomib for use in the treatment of lupus
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The present invention provides a method for treating lupus in a subject, comprising the step of administering to the subject Compound A.
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Page/Page column 20
(2016/06/06)
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- Electron-deficient heteroarenium salts: An organocatalytic tool for activation of hydrogen peroxide in oxidations
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A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pKR+ values (pKR+ red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.
- ?turala, Ji?í,Bohá?ová, Soňa,Chudoba, Josef,Metelková, Radka,Cibulka, Radek
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p. 2676 - 2699
(2015/03/18)
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- Amide-tethered organosilatranes: Syntheses, structural characterization and photophysical properties
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A series of trimethoxysilanes and silatranes coupled with distinct aromatic moieties (biphenyl, thiophene, pyrazine and pyridine) through amide linkage are reported. The synthetic approach involved the amidation of 3-aminopropyltrimethoxysilane (APTMS) with various carboxylic acids via acid chlorides (1a-1g) to generate amidopropylsilanes (2a-2g). Transesterification of the resultant silanes with triethanolamine and tris(isopropanolamine) yielded unsubstituted (3a-3g) and 3,7,10-trimethylsubstitued organosilatranes (4a-4g), respectively. The compounds were successfully characterized by various spectroscopic techniques [IR, NMR (1H, 13C) and Mass] and elemental analysis. The complete structure elucidation for compounds 3a, 3c·H2O and 3f was carried out using single crystal X-ray diffraction analysis. The photophysical response was studied by UV-Vis absorption and fluorescence spectroscopy. These organosilatranes possess metal ion binding sites and can be put forth for advanced analytical applications.
- Singh, Gurjaspreet,Rani, Sunita,Saroa, Amandeep,Promila,Arora, Aanchal,Choquesillo-Lazarte, Duane
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supporting information
p. 78 - 91
(2015/06/02)
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- THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE
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Methods of treating disorders using compounds that modulate striatal-enriched tyrosine phosphatase (STEP) are described herein. Exemplary disorders include schizophrenia and cognitive deficit.
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Paragraph 1603
(2015/11/16)
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- Salicylanilide pyrazinoates inhibit in vitro multidrug-resistant Mycobacterium tuberculosis strains, atypical mycobacteria and isocitrate lyase
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The development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial active salicylanilides and pyrazinoic acid (POA), an active metabolite of pyrazinamide, in which these esters are likely hydrolysed without presence of pyrazinamidase/nicotinamidase. Minimum inhibitory concentrations (MICs) of the esters were within the range 0.5-8 μmol/l for Mycobacterium tuberculosis and 1-32 μmol/l for nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium kansasii). All esters showed a weak inhibition (8-17%) of isocitrate lyase at the concentration of 10 μmol/l. The most active pyrazinoates showed MICs for multidrug-resistant tuberculosis strains in the range of 0.125-2 μmol/l and no cross-resistance with clinically used drugs, thus being the most in vitro efficacious salicylanilide esters with 4-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate superiority (MICs ≤ 0.25 μmol/l). This promising activity is likely due to an additive or synergistic effect of released POA and salicylanilides. Selectivity indexes for the most active salicylanilide pyrazinoates ranged up to 64, making some derivatives being attractive candidates for the next research; 4-bromo-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate showed the most convenient toxicity profile.
- Krátky, Martin,Vin?ová, Jarmila,Novotná, Eva,Stola?íková, Ji?ina
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- Rhodium(III)-catalyzed oxidative olefination of picolinamides: Convenient synthesis of 3-alkenylpicolinamides
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A rhodium(III)-catalyzed selective olefination of picolinamide derivatives has been developed. The reaction shows high regioselectivity, low catalyst loading (0.5 mol%), high yield and good functional group tolerance, providing a convenient strategy for the synthesis of 3-alkenylpicolinamides.
- Zhou, Jun,Li, Bo,Qian, Zhen-Chao,Shi, Bing-Feng
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supporting information
p. 1038 - 1046
(2014/04/03)
-
- C-H activation by amide chelation control: Ruthenium-catalyzed direct synthesis of 2-Aryl-3-furanamides
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A new, catalytic methodology for the synthesis of heterobiaryls by the ruthenium-catalyzed C-H activation/cross-coupling of heterocyclic amides with aryl boroneopentylates is surveyed. From this survey, the highly regioselective reaction of furan-3-carboxamide to give 2-aryl-3-furanamides is optimized and generalized in scope with respect to the aryl boroneopentylate coupling partners. Established thereby is a one-step synthetic method which may supercede the broadly applied two-step directed ortho metalation (DoM)-cross coupling reaction involving cryogenic and strong base conditions and which has potential for further ortho and remote metalation chemistry.
- Zhao, Yigang,Snieckus, Victor
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supporting information
p. 1527 - 1532
(2014/06/09)
-
- Rh(III)-catalyzed cascade oxidative olefination/cyclization of picolinamides and alkenes via C-H activation
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Rh(III)-catalyzed cascade oxidative alkenylation/cyclization of picolinamides and alkenes to furnish pyrido pyrrolone derivatives is described, in which three C-H bonds and one N-H bond broke, while one C-C bond and one C-N bond formed. The reaction proceeded with high yield and high regioselectivity and stereoselectivity. Moreover, copper acetate can also be used in catalytic amounts with O2 serving as the terminal oxidant.
- Cai, Shangjun,Chen, Chao,Shao, Peng,Xi, Chanjuan
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supporting information
p. 3142 - 3145
(2014/06/23)
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- 3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents
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Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC90 value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.
- Yang, Jianzhong,Pi, Weiyi,Xiong, Li,Ang, Wei,Yang, Tao,He, Jun,Liu, Yuanyuan,Chang, Ying,Ye, Weiwei,Wang, Zhenling,Luo, Youfu,Wei, Yuquan
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supporting information
p. 1424 - 1427
(2013/03/14)
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- Decarbonylative C-H coupling of azoles and aryl esters: Unprecedented nickel catalysis and application to the synthesis of muscoride A
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A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.
- Amaike, Kazuma,Muto, Kei,Yamaguchi, Junichiro,Itami, Kenichiro
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supporting information; experimental part
p. 13573 - 13576
(2012/10/08)
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- Synthesis and antitubercular evaluation of N-Arylpyrazine and N,Na-Alkyl-diylpyrazine-2-carboxamide derivatives
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Two series of pyrazinamide (PZA) derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Some compounds exhibited minimum inhibitory concentration activity of 50-100 μg/mL, greater than the first line antituberculosis drug PZA in Alamar Blue assay (>100 μg/mL). The obtained activities can be considered promising results, which characterizes these compounds as good start points to development of new antitubercular agents.
- Bispo, Marcelle De Lima Ferreira,Goncalves, Raoni Schroeder Borges,Lima, Camilo Henrique Da Silva,Cardoso, Laura Nogueira De Faria,Lourenco, Maria Cristina Silva,De Souza, Marcus Vinicius Nora
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p. 1317 - 1322
(2013/02/22)
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- Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): Potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts
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The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.
- Boulahjar, Rajaa,Ouach, Aziz,Matteo, Chiurato,Bourg, Stephane,Ravache, Myriam,Guével, Rémy Le,Marionneau, Séverine,Oullier, Thibauld,Lozach, Olivier,Meijer, Laurent,Guguen-Guillouzo, Christiane,Lazar, Sa?d,Akssira, Mohamed,Troin, Yves,Guillaumet, Gérald,Routier, Sylvain
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p. 9589 - 9606
(2013/01/16)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 156
(2011/04/24)
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- Photoinduced cleavage of N-N bonds of aromatic hydrazines and hydrazides by visible light
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A photocatalytic system involving [Ru(bpyrz)(PFH, visible light, and air has been developed for cleavage of the N-N bonds of hydrazines and hydrazides. This catalytic system is generally effective for N,N-disubstituted hydrazine and hydrazide derivatives, including arylhydrazides, N-alkyl-N-arylhydrazines, and N,N-diarylhydrazines. The utility of this cleavage reaction has been demonstrated by synthesizing a variety of secondary aromatic amines. Georg Thieme Verlag Stuttgart ? New York.
- Zhu, Mingzhao,Zheng, Nan
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supporting information; experimental part
p. 2223 - 2236
(2011/09/15)
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- PROTEASOME INHIBITORS AND PROCESSES FOR THEIR PREPARATION, PURIFICATION AND USE
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The invention provides boronic esters of Formula (I) wherein R1, R2, R3, and R4 are as described herein, and methods for the preparation and purification thereof.
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Page/Page column 120
(2011/08/04)
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- Synthesis, antimycobacterial, antifungal and photosynthesis-inhibiting activity of chlorinated N-phenylpyrazine-2-carboxamides
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A series of sixteen pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings was synthesized by the condensation of chlorides of substituted pyrazinecarboxylic acids with ring-substituted (chlorine) anilines. The prepared compounds were characterized and evaluated for their antimycobacterial and antifungal activity, and for their ability to inhibit photosynthetic electron transport (PET). 6-Chloro-N-(4-chlorophenyl) pyrazine-2-carboxamide manifested the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 6-chloro-5-tert-butyl-N-(3,4-dichlorophenyl) pyrazine-2-carboxamide (MIC = 62.5 μmol/L). 6-Chloro-5-tert-butyl-N-(4- chlorophenyl)pyrazine-2-carboxamide showed the highest PET inhibition in spinach chloroplasts (Spinacia oleracea L.) chloroplasts (IC50 = 43.0 μmol/L). For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structureactivity relationships are discussed.
- Dolezal, Martin,Zitko, Jan,Osicka, Zdenek,Kunes, Jiri,Vejsova, Marcela,Buchta, Vladimir,Dohnal, Jiri,Jampilek, Josef,Kralova, Katarina
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experimental part
p. 8567 - 8581
(2011/03/20)
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- Substituted N-phenylpyrazine-2-carboxamides: Synthesis and antimycobacterial evaluation
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The condensation of chlorides of substituted pyrazinecarboxylic acids with ringsubstituted anilines yielded twelve substituted pyrazinecarboxylic acid amides. The synthetic approach, analytical, and lipophilicity data of the newly synthesized compounds are presented. Two antituberculosis assays were used. Firstly, the antimycobacterial activity against four different Mycobacterium strains in a series of pyrazine derivatives was investigated. Secondly, the antimycobacterial evaluation was performed at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) program. Interesting in vitro antimycobacterial activity was found, N-(3-iodo-4-methylphenyl) pyrazine-2-carboxamide (9) was most active derivative compound against M. tuberculosis (MIC 90 = 0.819 μg/mL).
- Dolezal, Martin,Zitko, Jan,Kesetovicova, Diana,Kunes, Jiri,Svobodova, Michaela
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experimental part
p. 4180 - 4189
(2009/12/28)
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- Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
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We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
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scheme or table
p. 6882 - 6889
(2010/07/03)
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- Synthesis and antimycobacterial evaluation of substituted pyrazinecarboxamides
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Unsubstituted, halogenated and/or alkylated pyrazine-2-carboxylic acid amides connected via -CONH- bridge with substituted anilines were synthesized using currently known synthetic pathways. The synthetic approach, analytical, spectroscopic, lipophilicity and biological data of 20 newly synthesized compounds are presented. Structure-activity relationships among the chemical structures, the antimycobacterial, antifungal, photosynthesis inhibiting and antialgal activity of the evaluated substituted N-phenylpyrazine-2-carboxamides are discussed. 5-tert-Butyl-6-chloro-N-(3-trifluoromethylphenyl)pyrazine-2-carboxamide (19) has shown the highest activity against Mycobacterium tuberculosis H37Rv (MIC = 3.13 μg/mL). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for N-(3-trifluoromethylphenyl)pyrazine-2-carboxamide (14, MIC = 62.5 μmol/mL). The highest reduction of chlorophyll content in Chlorella vulgaris was found for pyrazine-2-carboxylic acid (3-trifluoromethylphenyl)amide (9, IC50 = 12.1 μmol/L).
- Dolezal, Martin,Cmedlova, Pavlina,Palek, Lukas,Vinsova, Jarmila,Kunes, Jiri,Buchta, Vladimir,Jampilek, Josef,Kralova, Katarina
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p. 1105 - 1113
(2008/09/20)
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- Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors
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A series of novel l-lysine derivatives were designed, synthesized, and assayed for their inhibitory activities on amino-peptidase N (APN)/CD13 and matrix metalloproteinase-2 (MMP-2). The preliminary biological test showed that most of the compounds displayed a high inhibitory activity against MMP-2 and a low activity against APN except compound B6 which exhibited good potency (IC50 = 13.2 μM) similar with APN inhibitor Bestatin (IC50=15.5 μM), and could be used as lead compound in the future.
- Wang, Qiang,Chen, Maoying,Zhu, Huawei,Zhang, Jie,Fang, Hao,Wang, Binghe,Xu, Wenfang
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p. 5473 - 5481
(2008/12/21)
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- Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action
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The related 3C and 3C-like proteinase (3Cpro and 3CLpro) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3Cpro. Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3Cpro with Kics of 120-240 nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3Cpro and SARS 3CLpro, confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acyl-enzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modification in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3Cpro.
- Huitema, Carly,Zhang, Jianmin,Yin, Jiang,James, Michael N.G.,Vederas, John C.,Eltis, Lindsay D.
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p. 5761 - 5777
(2008/12/21)
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- NOVEL ANTHRANILIC ACID DERIVATIVE AS POTENTIAL ANTICANCER AGENT AND A PROCESS FOR THE PREPARATION THEREOF
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The present invention provides novel anthranilic acid derivative useful as potential anticancer agent. More particularly, the present invention relates novel anthranilic acid derivative of general formula (8), R' = alkyl-2-methoxyphenyl piperazine (or) benzyl, R = 2 mthoxy phenyl, piperazine, 2-pyridyl piperazine, 2-pyrimidyl piperazine, 4-quinazolinyI piperazine, 9H-9-fluorenylamine, 4-{(2{amino-5-(methoxy)-4-[(phenylmethyl)oxy]phenyl} carbonyl)hexahydro-1-pyrazinyl], and [(4[2amino-4-(benzyloxy)-5-methoxybenzoyl] aminophenyI)sulfonyl]-4-benzamine; X = H (or) pyrazine-2-carbonyl. The present invention also provides a process for the preparation of novel anthranilic acid derivative of general formula (8), which is useful as potential anticancer agent.
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Page/Page column 20
(2008/12/07)
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- Synthesis and in vitro activity towards Mycobacterium tuberculosis of L-serinyl ester and amino derivatives of pyrazinoic acid
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Reactions between either L-serine methyl ester hydrochloride (1), or the cbz derivative, methyl (S)-(+)-2-(benzyloxycarbonylamino)-3-hydroxypropanoate (2), and pyrazinoyl chloride (3), have been studied. Methyl (S)-(+)-2- benzyloxycarbonylamino-3-[(pyrazinecarbonyl)oxy]propionate (4), methyl (S)-(+)-3-hydroxy-2-[(pyrazine-2-carbonyl) aminolpropionoate (7), methyl 2-[(pyrazinecarbonyl)amino]acrylate (8) were obtained. Additional products, methyl (S)-(+)-2-benzyloxycarbonylamino-3-formyloxypropionoate (5) and methyl (R)-(+)-2-benzyloxycarbonylamino-3-chloropropionoate (6), were isolated from reaction of 2 with 3, in the presence of DMF remaining from the preparation of 3, from pyrazinecarboxylic acid. The coupling of pyrazinecarboxylic acid with 1, in the presence of DCC was prevented by the formation of the unreactive adduct between DCC and pyrazinoic acid. The compounds were tested against M. tuberculosis: compounds (8) and (6) exhibited a MIC (μg/ml) value of 50 and 100, respectively, compared to the MIC value of 100 for the first line TB drug, pyrazinamide. The confirmation of the structure of (8) was obtained via X-ray crystallography.
- Pinheiro, Alessandra C.,Kaiser, Carlos R.,Lourenco, Maria C.S.,De Souza, Marcus V. N.,Wardell, Solange M.S.V.,Wardell, James L.
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p. 180 - 184
(2008/02/08)
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- 2-Amido-4-phenylthiazole Derivatives, The Preparation And The Therapeutic Use Thereof
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The disclosure relates to 2-amido-4-phenylthiazole derivatives of general formula (I) below: in which R1, R2, R3, Y, m, n, and p are as defined in the disclosure; as well as to their isomers, salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic use thereof.
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Page/Page column 17
(2008/06/13)
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- Preparation of novel antibacterial agents. Replacement of the central aromatic ring with heterocycles
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Discovery of novel antibacterial agents is a significant challenge. We have recently reported on our discovery of novel antibacterial agents in which we have rapidly optimized potency utilizing a parallel chemistry approach. These advanced leads suffer from high affinity for human serum albumin (HSA). In an effort to decrease the affinity for HSA we have prepared a series of heterocyclic analogs, which retained antibacterial activity and demonstrated reduced affinity for HSA.
- Li, Jianke,Wakefield, Brian D.,Ruble, J. Craig,Stiff, Cory M.,Romero, Donna L.,Marotti, Keith R.,Sweeney, Michael T.,Zurenko, Gary E.,Rohrer, Douglas C.,Thorarensen, Atli
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p. 2347 - 2350
(2008/12/21)
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- VESICULAR FORMULATIONS CONTAINING ORGANIC ACID PRODRUGS, PROCESS FOR THEIR PREPARATION, NEW PRODRUGS, PHARMACEUTICAL COMPOSTIONS AND METHOD FOR THE TREATMENT OF TUBERCULOSIS AND OTHER MYCOBACTERIOSIS
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The present invention relates to vesicular formulations containing a prodrug, characterized for comprising the combination of a prodrug of weak organic acids having the following general formula: R1COOH (I) or R1SO2H (II) wherein R1 is preferably selected from the group containing a benzenic, pyridinic, pyrazinic or pyrimidinic aromatic ring, or a linear chain substituted or unsubstituted, saturated or unsaturated, such as benzoic, benzenesulphinic, cinnamic, salicylic, pyrazinoic, nicotinic, carboxylic pyridazine and carboxylic pyrimidine, caproic, caprylic, capric, lauric, myristic, palmitic and estearic acids; with a liposomal or micellar carrier, which protects the prodrug from plasma degradation. The invention further relates to the process of preparation of liposomal formulations, novel prodrugs and pharmaceutical compositions intended for use in the treatment of tuberculosis and other mycobacterioses .
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Page/Page column 15-16
(2008/06/13)
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- Substituted pyrazinecarboxamides: Synthesis and biological evaluation
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Condensation of the corresponding chlorides of some substituted pyrazine-2-carboxylic acids (pyrazine-2-carboxylic acid, 6-chloropyrazine-2- carboxylic acid, 5-tertbutylpyrazine-2-carboxylic acid or 5-tert-butyl-6- chloropyrazine-2-carboxylic acid) with various ring-substituted aminothiazoles or anilines yielded a series of amides. The syntheses, analytical and spectroscopic data of thirty newly prepared compounds are presented. Structure-activity relationships between the chemical structures and the antimycobacterial, antifungal and photosynthesis-inhibiting activity of the evaluated compounds are discussed. 3,5-Bromo-4-hydroxyphenyl derivatives of substituted pyrazinecarboxylic acid, 16-18, have shown the highest activity against Mycobacterium tuberculosis H37Rv (54-72% inhibition). The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 5-tert-butyl-6-chloro-N-(4- methyl-1,3-thiazol-2-yl)pyrazine-2-carboxamide (8, MIC = 31.25 μmol·mL-1). The most active inhibitors of oxygen evolution rate in spinach chloroplasts were the compounds 5-tert-butyl-6-chloro-N-(5- bromo-2-hydroxyphenyl)-pyrazine-2-carboxamide (27, IC50 = 41.9 μmol·L-1) and 5-tert-butyl-6-chloro-N-(1,3-thiazol-2-yl)- pyrazine-2-carboxamide (4, IC50 = 49.5 μmol·L -1).
- Dolezal, Martin,Palek, Lukas,Vinsova, Jarmila,Buchta, Vladimir,Jampilek, Josef,Kralova, Katarina
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p. 242 - 256
(2007/10/03)
-
- Pyrazolyl inhibitors of 15- lipoxygenase
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The present invention provides pyrazolyl inhibitors of 15-LO, pharmaceutical compositions containing such inhibitors and methods for treating diseases related to the 15-LO cascade using such compounds and compositions.
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Page/Page column 13
(2010/02/11)
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- Novel Chimeric Scaffolds to Extend the Exploration of Receptor Space: Hybrid β-D-Glucose-Benzoheterodiazepine Structures for Broad Screening. Effect of Amide Alkylation on the Course of Cyclization Reactions
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New molecular platforms which are hybrids of two scaffolds-namely, β-D-glucose and benzodiazepine, each able to bind several proteins-were designed, synthesized and functionalized to serve as probes for broad biological screening. Herein, we describe the syntheses and chemical properties of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and (-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction conditions, even at concentrations of only 0.001 N. Consideration of factors affecting the conformation of amide bonds and their effects on cyclization reactions led us to alkylate the amide bond. As expected, the cyclization of the N-methyl derivative (-)-110 afforded exclusively the unimolecular cyclization product (+)-111. These compounds are only now undergoing broad screening and represent therefore at present a "prospecting library".
- Abrous, Leila,Jokiel, Patrick A.,Friedrich, Sarah R.,Hynes Jr., John,Smith III, Amos B.,Hirschmann, Ralph
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p. 280 - 302
(2007/10/03)
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- Anthranilic acid based CCK1 antagonists: The 2-indole moiety may represent a "needle" according to the recent homonymous concept
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Recently we described an innovative class of non-peptide CCK1 antagonists keeping appropriate pharmacophoric groups on the anthranilic acid employed as a molecular scaffold. The lead compound obtained, VL-0395, characterized by the presence of Phe and the 2-indole moiety at the C- and N-termini of anthranilic acid, respectively, is endowed with submicromolar affinity towards CCK1 receptors. Thus, we have prepared and tested on CCK receptors a library of VL-0395 analogues in order to investigate the precise topological and essential key interactions of the 2-indole group of the lead with the CCK1 receptor. The obtained results confirm that this group establishes very specific interactions with this receptor sub-site and may be viewed as a "needle" group.
- Varnavas, Antonio,Lassiani, Lucia,Valenta, Valentina,Berti, Federico,Tontini, Andrea,Mennuni, Laura,Makovec, Francesco
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