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Triazolo
Selected AbstractsSynthesis, Cytotoxicity by Bioluminescence Inhibition, Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5- c]quinazolin-2-ylthio)carboxylic Acid AmidesARCHIV DER PHARMAZIE, Issue 11 2009Lyudmila N. Antipenko Abstract We report in this work the synthesis, cytotoxicity, and antimicrobial activity of ([1,2,4]triazolo[1,5- c]quinazolin-2-ylthio)carboxylic acid amides 4,7 in connection with our previous research in the preparation of triazoloquinazoline derivatives. Due to simplicity, general availability of starting materials, and high yields, the most reliable method of synthesis appeared to be the one with N,N -carbonyldiimidazole activation stage. The chemical structures of all obtained substances were deduced from FT-IR, 1H-NMR, EI-MS, and LC-MS spectral data. The results of cytotoxicity evaluated by bioluminescence inhibition of bacterium Photobacterium leiognathi, strain Sh1 showed that compounds 4.1, 4.6, and 6.1 were the most cytotoxic. Investigation of the antimicrobial and antifungal activity of amides 4,7 (concentration 5 mg/mL) was carried out by the stiff-plate agar-diffusion method. We found that the compounds possessed low (4.1, 4.7) antifungal activity against Candida tenuis and strong (4.21, 5.1, 5.9) or inefficient (4.7, 4.12, 4.16) activity against Aspergillus niger. Substances 5.1 and 5.9 slightly affected Mycobacterium luteum. Staphylococcus aureus was resistant to all obtained substances, and only the n -butyramide derivatives 7.1 and 7.5 inhibited the growth of Escherichia coli. Hence, there was no strong correlation between bioluminescence inhibition and antimicrobial activity of the investigated substances. [source] ChemInform Abstract: Copper-Catalyzed Tandem Synthesis of [1,2,3]Triazolo[5,1-a]isoquinolines and Their Transformation to 1,3-Disubstituted Isoquinolines.CHEMINFORM, Issue 18 2010Yuan-Yuan Hu Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Vilsmeier,Haack Formylation of Acetonitrile Revisited: Synthesis of Novel Pyrazolo[1,5-a]pyrimidines and Triazolo[1,5-a]pyrimidine.CHEMINFORM, Issue 37 2009Maruti G. Ghagare Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: anti-HAV Activity of Some Newly Synthesized Triazolo[4,3-b]pyridazines.CHEMINFORM, Issue 32 2008Ahmed H. Shamroukh Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] 4-Substituted Anilino Imidazo[1,2-a] and Triazolo[4,3-a]quinoxalines.CHEMINFORM, Issue 4 2007Evaluation of in vitro Biological Activity., Synthesis Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Synthesis and Chemical Transformations of Partially Hydrogenated [1,2,4]Triazolo[5,1-b]quinazolines.CHEMINFORM, Issue 48 2006V. V. Lipson Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Synthesis of New [1,2,4]Triazolo and [1,2,4]Oxadiazolo[1,3,4]benzotriazepines.CHEMINFORM, Issue 44 2002T. El Messaoudi Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Synthesis and Bioactivity of Novel Triazolo[1,5-a]pyrimidine Derivatives.CHEMINFORM, Issue 3 2002Guangfu Yang Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of 11H-[1,2,4]Triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones.CHEMINFORM, Issue 13 2001Maria Zappala Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] An Efficient Synthesis of [1, 2, 4]Triazolo[3, 2=d][1, 5]benzoxazepin-2-thiones, a Kind of Novel Tricyclic O, N -HeterocyclesCHINESE JOURNAL OF CHEMISTRY, Issue 3 2004Zheng Li Abstract A series of novel tricyclic O, N -heterocycles, [1, 2, 4]triazolo[3.2- d][1, 5]benzoxazepin-2-thiones 7 were achieved via acid-induced ring closure of the geminal arylazo isothiocyanate compounds 5 which were derived from substituted chroman-4-ones. followed by feasible ring expansion with simultaneous insertion of the nitrogen atom into the carbon skeleton. The X-ray crystal structure of 7d was also described. [source] [(Pyridylcarbonyl)pyridyl]triazolopyridines, Useful Ligands for the Construction of Polynuclear Coordination Compounds , Synthesis, Crystal Structure and Magnetic Properties of a Novel Tetranuclear Copper(II) Cubane,EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 29 2007Belén Abarca Abstract A new tetranuclear cubane Cu4O4 complex has been synthesised from assembly of CuII ions and the polydentate ligand (pyridin-2-yl){6-([1,2,3]triazolo[1,5- a]pyridin-3-yl)pyridin-2-yl}methanone. Crystallographic analysis indicates that the Cu4O4 unit has an S4 symmetry. The magnetic properties have been analysed using the H = ,2,i,jJijSiSj spin Hamiltonian. Two distinct coupling constants, 2J1,3 = ,37.4 cm,1 and 2J1,2 = ,2.6 cm,1, obtained from the fitting of the experimental data have been rationalised on the basis of a density functional study of magnetostructural correlations in cubane complexes containing the Cu4O4 core. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] N -Phenyl-1,2,4-triazoline-3,5-dione (PTAD) as a Dienophilic Dinitrogen Equivalent: A Simple Synthesis of 3-Amino-1,2,4-benzotriazines from Arylcarbodiimides,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 4 2010Mateo Alajarin Abstract N -Arylcarbodiimides react with PTAD to provide [1,2,4]triazolo[1,2- a][1,2,4]benzotriazines by a [4+2] cycloaddition reaction. When asymmetrically substituted diarylcarbodiimides are used, the cycloaddition proceeds with total chemoselectivity because only the more electron-rich aryl nucleus is involved. This observation has been rationalized by a computational study using DFT methods that shows that, in the reaction of HTAD with arylcarbodiimides, the magnitude of the energy barriers depend on the electronic features of the substituents at the aryl nucleus; the calculations also indicate that the reaction proceeds through asynchronous states with polar characteristics. The treatment of the final cycloadducts with potassium hydroxide affords 3-aryl(alkyl)amino-1,2,4-benzotriazines. [source] First Propargyl Azides Bearing Strong Acceptor Substituents and Their Effective Conversion into Allenyl Azides: Influence of the Electronic Effects of Substituents on the Reactivity of Propargyl Azides,,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 17 2005Joseph Rodolph Fotsing Abstract We have succeeded in the synthesis of propargyl azides containing 1- or 3-phenylthio functionalities. The selective oxidation of their sulfur atoms to sulfoxides and sulfones allows access to the first propargyl azides bearing acceptor substituents. Interestingly, the prototropic rearrangement of the latter propargyl azides leads to the formation of allenyl azides with relatively high stabilities and with moderate to good yields. Propargyl azides containing phenylthio functionalities react in the presence of nucleophiles to afford the expected N -unsubstituted 1,2,3-triazoles via short-lived allenyl azides. These results are entirely different from those of the corresponding sulfoxides and sulfones, which react under the analogous conditions either to produce the corresponding bis(triazolo)pyrazine derivatives or to yield newly substituted vinyl azides. The latter compounds can successfully be used as starting material providing access to azirines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] An expedient synthesis of novel, fused pyrimido[4,5- d]pyrimidine and pyrimido [5,4- e] [1,2,4]triazolo[4,3- c]pyrimidine analogues from 4-amino-2,6-dichloro-pyrimidineHETEROATOM CHEMISTRY, Issue 4 2006Pratibha Sharma A number of potent pyrimido[4,5-d]pyrimidine have efficiently been synthesized by the condensation of 4-amino-2,6-dichloropyrimidine with various substituted benzaldehyde followed by cyclization with ammonium thiocyanate. Also, these newly synthesized derivatives were utilized for the construction of novel pyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine analogues via oxidative cyclization involving 1,5-hydrogen abstraction. Structure of all the newly constructed derivatives was corroborated by the elemental and spectral data. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:245,253, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20177 [source] Indolizines, triazolo[4,3- a]pyridines, benzimidazo[1,2- d]oxadiazoles, and pyrazolo[1,5- c]triazoles via nitrogen and sulfur ylidesHETEROATOM CHEMISTRY, Issue 6 2004Kamal M. Dawood The pyridinium salts 2a,b reacted with dimethyl acetylenedicarboxylate (DMAD) to give the indolizine derivatives 6a,b. Pyridinium salts 2a,b also reacted with pyrazole-5-diazonium salt to afford the hydrazonoyl bromides 8a,b, which on treatment with aqueous ethanolic sodium carbonate furnished the 8aH -1,2,4-triazolo[4,3- a]pyridine 10. When sulfonium bromide 11 was treated with nitrous acid and with pyrazole-5-diazonium salt, it afforded the new hydroximoyl and hydrazonoyl halides 12 and 17, respectively. Compound 12 reacted with 2-methylthiobenzimidazole to furnish benzimidazo[1,2- d]-1,2,4-oxadiazole derivative 14. Treatment of either 12 with 3-phenyl-5-aminopyrazole or 17 with triethylamine resulted in the formation of the same product: pyrazolo[1,5- c]-1,2,4-triazole derivative 16. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:432,436, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20037 [source] Synthesis of 2,3-dihydro-1,3,4-thiadiazole, thiazole, and triazolo[4,3- a]pyrimidine derivatives from ethyl benzoylacetateHETEROATOM CHEMISTRY, Issue 2 2004Nora M. Rateb Thiophene and thiazole derivatives can be obtained from potassium salt of ethyl 3-oxo-3-phenyl-2-[(phenylamino)thioxomethyl]propanoate and ethyl chloroacetate in N,N -dimethylformamide solution under different conditions. 2,3-Dihydro-1,3,4-thiadiazoles and triazolo[4,3- a]pyrimidine were obtained from reaction of hydrazonoyl halides with each of thioanilide and pyrimidine-2-thione, respectively. Structures of the newly synthesized compounds were elucidated on the basis of elemental analysis, spectral data, and alternative synthesis route whenever possible. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:107,113, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10222 [source] Heterocyclic synthesis containing bridgehead nitrogen atom: Synthesis of 3-[(2H)-2-oxobenzo[b]pyran-3-yl]- s -triazolo[3,4- b]-1,3,4-thiadiazine and thiazole derivativesHETEROATOM CHEMISTRY, Issue 2 2003M. A. Raslan The reaction of 2H-2-oxobenzo[b]pyran-3-hydrazide (2) with carbon disulfide in basic DMF afforded potassium thiocarbamate 3, which readily underwent heterocyclization upon its reaction with hydrazine and/or phenacyl bromide to yield 1,2,4-tiazole (4) and thiazole 7 derivatives, respectively. Condensation of 4 with substituted phenacyl bromide and/or chloranil gave 1,2,4-triazole[3,4-b]thiadiazine (5a,b) and 3,10-bis-[2H-2-oxobenzo[b]pyran-3-yl]-6,13-dichloro-bis-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazino[5,,6,-b:5,,6,-e]cyclohexa-1,4-diene (6), respectively. Cyclization of thiosemicarbazide 10 by refluxing it in sodium hydroxide and/or phosphoryl chloride afforded triazole 13 and thiadiazole 15 derivatives, respectively. Also, 10 reacted with phenacyl bromide in the presence of anhydrous sodium acetate to give the oxothiazolidine derivative 17. The structure of the synthesized compounds were confirmed by elemental analyses, IR, 1H NMR, and mass spectra. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:114,120, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10109 [source] Copper(I)-Catalyzed Synthesis of Novel 4-(Trifluoromethyl)-[1,2,3]triazolo[1,5- a]quinoxalines via Cascade Reactions of N -(o -Haloaryl)alkynylimine with Sodium AzideADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 8 2010Zixian Chen Abstract Novel tricyclic 4-(trifluoromethyl)-[1,2,3]triazolo[1,5- a]quinoxalines were readily prepared from N -(o -haloaryl)alkynylimines and sodium azide via copper(I)-catalyzed tandem reactions. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery. [source] Synthesis and herbicidal activity of O,O -dialkyl N -[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yloxy)benzoxyl]-1-amino-1-substitutedbenzyl phosphonatesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 1 2010Wu Tang A series of novel 1,2,4-triazolo[1,5-a]pyrimidine derivatives containing an ,-amino phosphonate moiety 5 were designed and synthesized by the multi-step reactions. Their structures were clearly confirmed by spectroscopic data (IR, 1H NMR, 31P NMR, MS) and elemental analysis, compound 5b was further determined by X-ray diffraction crystallography. The results of preliminary bioassay indicated that some of the title compounds 5 possessed moderate herbicidal activities against dicotyledonous plants (Brassica campestris L) at the concentration of 100 mg/L. For example, compound 5i possessed 92.0% inhibitory activity against B. campestris L and showed better activity than that of the commercialized herbicide Bispyribac-sodium; however, compounds 5 displayed weak herbicidal activity at the concentration of 10 mg/L. J. Heterocyclic Chem., (2010). [source] Synthesis of novel pyrazolo[3,4- d]pyridazine, pyrido[1,2- a]benzimidazole, pyrimido[1,2- a]benzimidazole and triazolo[4,3- a]pyrimidine derivativesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 6 2008Mohamed R. Shaaban 4-Acetyl-5-methyl-1-phenyl-1H -pyrazole reacts with dimethylformamide dimethylacetal (DMF-DMA) to afford the corresponding (E)1-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-3-(N,N -dimethylamino)-2-propen-1-one. The latter product undergoes regioselective 1,3-dipolar cycloaddition with nitrilimines and nitrile oxides to afford the novel 3-aroyl-4-(5-methyl-1-phenyl-1H -pyrazol-4-yl)carbonyl-1-phenylpyrazole and 3-aroyl-4-(5-methyl-1-phenyl-1H -pyrazol-4-yl)carbonyl isoxazole derivatives, respectively. It reacts also with 1H -benzimidazole-2-acetonitrile, 2-aminobenzimidazole and 3-amino-1,2,4-triazole to afford the novel pyrido[1,2- a]benzimidazole, pyrimido[1,2- a]benzimidazole and the triazolo[4,3- a]pyrimidine derivatives, respectively. The reaction of 3-aroyl-4-(5-methyl-1-phenyl-1H -pyrazol-4-yl) carbonyl-1-phenylpyrazole derivatives with hydrazine hydrate led to a new pyrazolo[3,4- d]pyridazine derivatives. [source] Synthesis, structure and some reactions of 4a',5,,6,,7,,8,,8a'-hexahydro-4,H -spiro[cyclohexane-1,9,-[1,2,4]triazolo[5,1- b]-quinazolines]JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2008Victor M. Chernyshev 2,-Substituted 5,,6,,7,,8,-tetrahydro-4,H -spiro[cyclohexane-1,9,-[1,2,4]triazolo[5,1- b]quinazolines] 3a-d were synthesized by condensation of 3-substituted 5-amino-1,2,4-triazoles 1a-d with 2-cyclohexylidene cyclohexanone 2 in DMF. The compounds 3 were hydrogenated with sodium borohydride in ethanol to give 2,-substituted cis -4a',5,,6,,7,,8,,8a'-hexahydro-4,H -spiro[cyclohexane-1,9,-[1,2,4]triazolo[5,1- b]quinazolines] 4a-d in high yields. The reactions of alkylation, acylation and sulfonylation of the compounds 4 were studied. The structure of the synthesized compounds was determined on the basis of NMR measurements including HSQC, HMBC, NOESY techniques and confirmed by the X-ray analysis of 6 and 11b. The described synthetic protocols provide rapid access to novel and diversely substituted hydrogenated [1,2,4]triazolo[5,1- b]quinazolines. [source] Synthesis and reactions of 3-amino-2-methyl-3H -[1,2,4]triazolo[5,1- b]-quinazolin-9-one and 2-hydrazino-3-phenylamino-3H -quinazolin-4-oneJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 6 2003Mohamed A. Saleh The reaction of 3- N -(2-mercapto-4-oxo-4H -quinazolin-3-yl)acetamide (1) with hydrazine hydrate yielded 3-amino-2-methyl-3H -[1,2,4]triazolo[5,1- b]quinazolin-9-one (2). The reaction of 2 with o -chlorobenzaldehyde and 2-hydroxy-naphthaldehyde gave the corresponding 3-arylidene amino derivatives 3 and 4, respectively. Condensation of 2 with 1-nitroso-2-naphthol afforded the corresponding 3-(2-hydroxy-naphthalen-1-yl-diazenyl)-2-methyl-3H -[1,2,4]triazolo[5,1- b]quinazolin-9-one (5), which on subsequent reduction by SnCl2 and HCl gave the hydrazino derivative 6. Reaction of 2 with phenyl isothiocyanate in refluxing ethanol yielded thiourea derivative 7. Ring closure of 7 subsequently cyclized on refluxing with phencyl bromide, oxalyl dichloride and chloroacetic acid afforded the corresponding thiazolidine derivatives 8, 9 and 10, respectively. Reaction of 2-mercapto-3-phenylamino-3H -quinazolin-4-one (11) with hydrazine hydrate afforded 2-hydrazino-3-phenylamino-3H -quinazolin-4-one (12). The reactivity 12 towards carbon disulphide, acetyl acetone and ethyl acetoacetate gave 13, 14 and 15, respectively. Condensation of 12 with isatin afforded 2-[N -(2-oxo-1,2-dihydroindol-3-ylidene)hydrazino]-3-phenylamino-3H -quinazolin-4-one (16). 2-(4-Oxo-3-phenylamino-3,4-dihydroquinazolin-2-ylamino)isoindole-1,3-dione (17) was synthesized by the reaction of 12 with phthalic anhydride. All isolated products were confirmed by their ir, 1H nmr, 13C nmr and mass spectra. [source] Studies with enaminones: synthesis of new coumarin-3-yl azoles, coumarin-3-yl azines, coumarin-3-yl azoloazines, coumarin-3-yl pyrone and coumarin-2-yl benzo[b]FuransJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 4 2001Fathy Mohamed Abel Aziz El-Taweel 3-Acetylcoumarine was condensed with dimethylformamide dimethylacetal (DMFDMA) to yield the enaminone, which reacts readily with hydroxylamine and with hydrazines to yield coumarin-3-ylisoxazoles and coumarin-3-ylpyrazoles respectively. Reaction of the enaminone with benzamidine hydrochloride and 3-amino-1,2,4-1H -triazole affords the pyrimidine and triazolo[3,4- b]pyrimidine. The enaminone reacts with hippuric acid and with the dithiocarboxylic acid to yield pyranones. The reaction of the enaminone with 3-amino-1H -1,2,4-triazole gives the triazolo[3,4- b]pyrimidine. The enaminone underwent self dimerization on reflux in acetic acid ammonium acetate to yield the coumarinyl pyridines and reacted with ketone under the same conditions to yield the pyridine. The reaction of the enaminone with 1,4-benzoquinone and 1,4-naphthoquinone gives benzofuryl coumarine derivatives. [source] Synthesis of nitrogen-containing heterocycles 9,.JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 6 2000- a][, Preparation, ]-triazolo[, ]triazine] derivatives, carbon-carbon bond cleavage of spiro[cycloalkane[, related compounds Diaminomethylenehydrazones of cyclic ketones 1,5 reacted with ethyl N -cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1,,2,,4,]triazolo[1,,5,,- a][1,,3,-5,]triazine] derivatives 7,12 in moderate to high yields. Ring-opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2-alkyl-5-amino[1,2,4]triazolotriazines 13,16. Diaminomethylenehydrazones 17,19, of hindered acyclic ketones, gave 2-methyl-7-methylthio[1,2,4]-triazolo[1,5- a][1,3,5]triazines 21,23 by the reaction with II as the main products with apparent loss of 2-methylpropane from the potential precursor, 2- tert -butyl-2-methyl-7-methylthio[1,2,4]triazolo[1,5- a]-[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one-step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed. [source] Expression of CD73/ecto-5,-nucleotidase on human gingival fibroblasts and contribution to the inhibition of interleukin-1,-induced granulocyte-macrophage colony stimulating factor productionJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2004Eiji Nemoto Background and objectives:, CD73/5,-nucleotidase (5,-NT) is an ectoenzyme that participates in immune/inflammatory reactions. We examined the possible expression of CD73/5,-NT on human gingival fibroblasts (hGF), which are important to the immune/inflammatory system in periodontal tissue. Methods and results:, We demonstrated that CD73/5,-NT was expressed on hGF by flow cytometry. We found that pre-treatment of hGF with 5,-AMP induced marked inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) production from hGF upon stimulation with interleukin-1, (IL-1,) by enzyme-linked immunosorbent assay (ELISA). A specific inhibitor of 5,-NT, adenosine 5,-[,,,-methylene] diphosphate blocked the inhibition of GM-CSF production, suggesting that adenosine converted from 5,-AMP acts on the inhibitory effects. The GM-CSF inhibition suggested that A3 receptor might be involved. The rank order of agonists was found to be (N6 -benzyl-5,- N -ethylcarboxamidoadenosine) A3 receptor agonist , (2-chloroadenosine) non-selective agonist > (CGS-21680) A2A receptor agonist > adenosine , (N6 -cyclohexyladenosine) A1 agonist. Further support for the main role of A3 receptor was the binding A3 antagonist [9-chloro-2-(2-furanyl)-5-([phenylacetyl]amino)[1,2,4]-triazolo[1,5- c]quinazdine] reversed the effect of adenosine, but no significant reverse was observed by A1 (1,3-dipropyl-8-cyclopentylxanthine), A2 [3,7-dimethyl-1-(2-propargyl)xanthine], A2A[8-(3-chlorostyryl)caffeine], and A2B (alloxazine) antagonists. The CD73/5,-NT expression was increased upon stimulation with gamma-interferon, but not other stimulants such as tumor necrosis factor-alpha, IL-4, lipopolysaccharide from Porphyromonas gingivalis and Escherichia coli, and fimbriae from P. gingivalis, and this increase was correlated with the enhanced GM-CSF inhibition by 5,-AMP but not adenosine. Conclusions:, These findings suggested that CD73/5,-NT on hGF exerts an anti-inflammatory effects in periodontal disease by conversion from 5,-AMP to adenosine. [source] Synthesis and Antimycobacterial Activity of Azetidine-, Quinazoline-, and Triazolo-thiadiazole-containing PyrazinesARCHIV DER PHARMAZIE, Issue 4 2010Chandrakant G. Bonde Abstract The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for the discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of N -[2-(substituted aryl)-3-chloro-4-oxoazetidin-1-yl]-2-(pyrazin-2-yloxy)acetamide, 6-(substituted aryl)-3-[(pyrazin-2-yloxy)methyl][1,2,4]triazolo[3,4- b][1,3,4]thiadiazole, and N -[6-({2-[(pyrazin-2-yloxy)acetyl] hydrazino}sulfonyl)-2-methyl-4-oxo-1,4-dihydroquinazolin-3(2H)yl]-substituted aryl sulfonamides. The compounds were synthesized using the appropriate synthetic route. All synthesized compounds were assayed in vitro for antimycobacterial activity against the H37 Rv strain of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) was determined for the test compounds as well as for the reference standards. The compound which exhibited good antimycobacterial activity contains the substituents fluorine and methoxy. These electron-withdrawing or -donating substituents amend the lipophilicity of the test compounds which, in turn, alter the permeability across the bacterial cell membrane. Compounds 28, 37, and 43 showed good antimycobacterial activity while compound 51 showed a promising antimycobacterial activity. [source] Synthesis, Cytotoxicity by Bioluminescence Inhibition, Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5- c]quinazolin-2-ylthio)carboxylic Acid AmidesARCHIV DER PHARMAZIE, Issue 11 2009Lyudmila N. Antipenko Abstract We report in this work the synthesis, cytotoxicity, and antimicrobial activity of ([1,2,4]triazolo[1,5- c]quinazolin-2-ylthio)carboxylic acid amides 4,7 in connection with our previous research in the preparation of triazoloquinazoline derivatives. Due to simplicity, general availability of starting materials, and high yields, the most reliable method of synthesis appeared to be the one with N,N -carbonyldiimidazole activation stage. The chemical structures of all obtained substances were deduced from FT-IR, 1H-NMR, EI-MS, and LC-MS spectral data. The results of cytotoxicity evaluated by bioluminescence inhibition of bacterium Photobacterium leiognathi, strain Sh1 showed that compounds 4.1, 4.6, and 6.1 were the most cytotoxic. Investigation of the antimicrobial and antifungal activity of amides 4,7 (concentration 5 mg/mL) was carried out by the stiff-plate agar-diffusion method. We found that the compounds possessed low (4.1, 4.7) antifungal activity against Candida tenuis and strong (4.21, 5.1, 5.9) or inefficient (4.7, 4.12, 4.16) activity against Aspergillus niger. Substances 5.1 and 5.9 slightly affected Mycobacterium luteum. Staphylococcus aureus was resistant to all obtained substances, and only the n -butyramide derivatives 7.1 and 7.5 inhibited the growth of Escherichia coli. Hence, there was no strong correlation between bioluminescence inhibition and antimicrobial activity of the investigated substances. [source] Characterization of adenosine receptors mediating the vasodilator effects of adenosine receptor agonists in the microvasculature of the hamster cheek pouch in vivoAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2002J. Nicholls Summary 1 The aim of this study was to characterize the adenosine receptor mediating vasodilation in the microvasculature of the hamster cheek pouch in vivo. A range of adenosine agonists was used including N6 -cyclopentyladenosine (CPA) (A1 agonist), 5,- N -ethylcarboxamidoadenosine (NECA) (non-selective), 2-chloroadenosine (2CADO) (non-selective), 2- p -(2-carboxyethyl)-phenethylamino-5,- N -ethylcarboxamidoadenosine (CGS 21680) (A2A agonist), N6 -(3-iodobenzyl)-adenosine-5,- N -methyluronamide (IBMECA) (A3 agonist) and adenosine, as well as the adenosine antagonists 8-sulphophenyltheophylline (8-SPT) (A1/A2 antagonist), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (A1 antagonist) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) (A2A antagonist). 2 All the adenosine analogues used induced vasodilation at concentrations between 10 nm and 1 ,m, and the potency order was NECA > CGS 21680 > 2CADO > CPA=IBMECA >> adenosine, indicating an action at A2A receptors. 8-SPT (50 ,m) antagonized vasodilator responses to NECA with an apparent pKB of 5.4, consistent with an action at A1 or A2 receptors and confirming that A3 receptors are not involved in this response. 3 DPCPX (10 nm) had no effect on vasodilation evoked by NECA, suggesting that this response was not mediated via A1 receptors, while ZM 241385 (10 nm) antagonized dilator responses to NECA with an apparent pKB of 8.9 consistent with an action via A2A receptors. 4 Overall these results suggest that adenosine A2A receptors mediate vasodilation in the hamster cheek pouch in vivo. [source] Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine, a novel and selective p38, inhibitor: identification of an active metabolite in preclinical species and human liver microsomesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2006Amit S. Kalgutkar Abstract The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38,, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vdss) ranging from 0.4,1.3 l/kg (2.4,26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague-Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30,65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38, in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu,0.1,0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50>50 µM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent. Copyright © 2006 John Wiley & Sons, Ltd. [source] Brief, repeated, oxygen-glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Anna Maria Pugliese Ischemic preconditioning in the brain consists of reducing the sensitivity of neuronal tissue to further, more severe, ischemic insults. We recorded field epsps (fepsps) extracellularly from hippocampal slices to develop a model of in vitro ischemic preconditioning and to evaluate the role of A1, A2A and A3 adenosine receptors in this phenomenon. The application of an ischemic insult, obtained by glucose and oxygen deprivation for 7 min, produced an irreversible depression of synaptic transmission. Ischemic preconditioning was induced by four ischemic insults (2 min each) separated by 13 min of normoxic conditions. After 30 min, an ischemic insult of 7 min was applied. This protocol substantially protected the tissue from the irreversible depression of synaptic activity. The selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM), completely prevented the protective effect of preconditioning. The selective adenosine A2A receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3- a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385, 100 nM) did not modify the magnitude of fepsp recovery compared to control slices. The selective A3 adenosine receptor antagonists, 3-propyl-6-ethyl-5[ethyl(thio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate (MRS 1523, 100 nM) significantly improved the recovery of fepsps after 7 min of ischemia. Our results show that in vitro ischemic preconditioning allows CA1 hippocampal neurons to become resistant to prolonged exposure to ischemia. Adenosine, by stimulating A1 receptors, plays a crucial role in eliciting the cell mechanisms underlying preconditioning; A2A receptors are not involved in this phenomenon, whereas A3 receptor activation is harmful to ischemic preconditioning. British Journal of Pharmacology (2003) 140, 305,314. doi:10.1038/sj.bjp.0705442 [source] | |||||||||||||