- Transition metal complexes of 2-(2-(1H-benzo[d]imidazol-2-yl)hydrazono)propan-1-ol: Synthesis, characterization, crystal structures and anti-tuberculosis assay with docking studies
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Transition metal coordination complexes of Co(II), Ni(II), Cu(II) and Zn(II) with a newly designed ligand, 2-(2-(1H-benzo[d]imidazol-2-yl)hydrazono)propan-1-ol have been synthesized and characterized using various spectro-analytical techniques. The molecular structures of Co(II), Cu(II) and Zn(II) complexes are determined by single-crystal X-ray diffraction method. The metal to ligand stoichiometry has been found to be 1:2 in the case of Cobalt(II), Nickel(II) and Zinc(II) whereas 1:1 in the case of Copper(II) complex. The newly synthesized ligand and complexes have been assessed for their growth inhibiting potencies against H37Rv strain of Mycobacterium tuberculosis. The copper and cobalt complexes have emerged to be potent in vitro growth inhibitors of H37Rv. All the complexes are inhibiting the growth of other tested common microbial flora to a significantly lesser extent, making them selective towards H37Rv in the preliminary analysis. The consensus scores obtained by the docking studies of the molecules to the target protein enoyl acyl carrier protein reductase of M. tuberculosis H37Rv are in good agreement with the obtained MIC values.
- Kamat, Vinayak,Kokare, Dhoolesh,Naik, Krishna,Kotian, Avinash,Naveen,Dixit, Sheshagiri R.,Lokanath,Joshi, Shrinivas D.,Revankar, Vidyanand K.
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- Benzimidazolyl-pyrazolo[3,4- b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest
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1,3-Substituted pyrazolo[3,4-b]pyridinones 11-18 were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations. These compounds also selectively and potently inhibited growth of the MOLT-4 leukemia cell line. Subsequent structure-activity relationship studies determined the benzimidazolyl fragment as an essential pharmacophore for both effects. We applied numerous techniques for target identification. A preliminary QSAR target identification search did not result in tangible leads. Attempts to prepare a relevant photoaffinity probe that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and in in vitro panels of kinases and matrix metalloproteinases. Using a series of diverse modulators of spiculogenesis as standards, we excluded multiple signaling networks including Notch, Wnt/β-catenin, receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK as possible targets of 11. On the other hand, matrix metalloproteinase-9/hatching enzyme was identified as one potential target.
- Lichitsky, Boris V.,Komogortsev, Andrey N.,Dudinov, Arkady A.,Krayushkin, Mikhail M.,Khodot, Evgenii N.,Samet, Alexander V.,Silyanova, Eugenia A.,Konyushkin, Leonid D.,Karpov, Alexei S.,Gorses, Delphine,Radimerski, Thomas,Semenova, Marina N.,Kiselyov, Alex S.,Semenov, Victor V.
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- Effect of acetate and nitrate anions on the molecular structure of 3-(hydroxyimino)-2-butanone-2-(1H-benzimidazol-2-yl)hydrazone
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A novel Schiff base ligand 3-(hydroxyimino)-2-butanone-2-(1H-benzimidazol-2-yl)hydrazone has been synthesized by the condensation reaction of 2-Hydrazinobenzimidazole with diacetyl monoxime in presence of acetic acid catalyst. The ligand has crystallized as its acetate salt, due to the charge-assisted hydrogen bonding between protonated benzimidazole ring and acetate anion. Efforts to synthesize the zinc(II) complex of the title compound, has resulted in the formation of a nitrate salt of the ligand, instead of coordination complex of zinc(II). Acetate salt has crystallized in monoclinic P 21/n, while the nitrate salt has crystallized in a triclinic crystal system with P -1 space group. Hirshfeld surface analysis is presented for both of the crystal structures. Structures of synthesized molecules are even computationally optimized using DFT. A comparative structural approach between the synthesized molecules and DFT optimized structure of bare ligand without any counterions is analyzed in terms of bond parameters. Hydrogen bonding is explained keeping the anions as the central dogma. Mass fragmentation pattern of the organic molecule and comparative account of IR, 1H and 13C NMR chemical shifts are also presented. Compounds are screened for their antibacterial and antifungal potencies against few pathogenic microorganisms. The organic motif is found be an excellent antifungal agent.
- Kamat, Vinayak,Naik, Krishna,Revankar, Vidyanand K.
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- Design, synthesis, and antitumor activity of PLGA nanoparticles incorporating a discovered benzimidazole derivative as EZH2 inhibitor
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Purpose: Targeting enhancer of zeste homolog 2 (EZH2) can represent a hopeful strategy for oncotherapy. Also, the use of PLGA-based nanoparticles as a novel and rate-controlling carrier system was of our concern. Methods: Benzimidazole derivatives were synthesized, and their structures were clarified. In vitro antitumor activity was evaluated. Then, a modeling study was performed to investigate the ability of the most active compounds to recognize EZH2 active sites. Compound 30 (Drug) was selected to conduct pre-formulation studies and then it was incorporated into polymeric PLGA nanoparticles (NPs). NPs were then fully characterized to select an optimized formula (NP4) that subjected to further evaluation regarding antitumor activity and protein expression levels of EZH2 and EpCAM. Results: The results showed the antitumor activity of some synthesized derivatives. Docking outcomes demonstrated that Compound 30 was able to identify EZH2 active sites. NP4 exhibited promising findings and proved to keep the antitumor activity of Compound 30. HEPG-2 was the most sensitive for both Drug and NP4. Protein analysis indicated that Drug and NP4 had targeted EZH2 and the downstream signaling pathway leading to the decline of EpCAM expression. Conclusions: Targeting EZH2 by Compound 30 has potential use in the treatment of cancer especially hepatocellular carcinoma.
- Elkot, Hoda A.,Ragab, Ibrahim,Saleh, Noha M.,Amin, Mohamed N.,Al-Rashood, Sara T.,El-Messery, Shahenda M.,Hassan, Ghada S.
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- 1H-benzimidazole-2-yl hydrazones as tubulin-targeting agents: Synthesis, structural characterization, anthelmintic activity and antiproliferative activity against MCF-7 breast carcinoma cells and molecular docking studies
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In the present study, fifteen benzimidazolyl-2-hydrazones 7a-7o of fluoro-, hydroxy- and methoxy-substituted benzaldehydes and 1,3-benzodioxole-5-carbaldehyde were synthesized and their structure was identified by IR, NMR, and elemental analysis. The compounds 7j 2-(3-hydroxybenzylidene)-1-(5(6)-methyl-1H-benzimidazol-2-yl)hydrazone and 7i 2-(3-hydroxybenzylidene)-1-(1H-benzimidazol-2-yl)hydrazone have exerted the strongest anthelmintic activity (100% after 24 h incubation period at 37 °C) against isolated muscle larvae of Trichinella spiralis in an in vitro experiment. The in vitro cytotoxicity assay towards MCF-7 breast cancer cells and mouse embryo fibroblasts 3T3 showed that the studied benzimidazolyl-2-hydrazones exhibit low to moderate cytotoxic effects. The ability of the studied benzimidazolyl-2-hydrazones to modulate microtubule polymerization was confirmed and suggested that their anthelmintic action is mediated through inhibition of the tubulin polymerization likewise the other known benzimidazole anthelmitics. It was also shown that the four most promising benzimidazolyl-2-hydrazones do not affect significantly the AChE activity even at high tested concentration, thus indicating that they do not have the potential for neurotoxic effects. The binding mode of compounds 7j and 7n in the colchicine-binding site of tubulin were clarified by molecular docking simulations. Taken together, these results demonstrate that for the synthesized benzimidazole derivatives the anthelmintic activity against T. spiralis and the inhibition of tubulin polymerization are closely related.
- Anichina, Kameliya,Argirova, Maria,Tzoneva, Rumyana,Uzunova, Veselina,Mavrova, Anelia,Vuchev, Dimitar,Popova-Daskalova, Galya,Fratev, Filip,Guncheva, Maya,Yancheva, Denitsa
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- New 1H-benzimidazole-2-yl hydrazones with combined antiparasitic and antioxidant activity
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Parasitic infections, caused mainly by the speciesTrichinella spiralis(T. spiralis), are widespread around the world and lead to morbidity and mortality in the population. Meanwhile, some studies have showed that these parasites induce oxidative stress in the infected host. With the aim of developing a class of compounds combining anthelmintic with antioxidant properties, a series of new benzimidazolyl-2-hydrazones5a-l, bearing hydroxyl- and methoxy-groups, were synthesized. The anthelmintic activity on encapsulatedT. spiraliswas studiedin vitrothus indicating that all hydrazones were more active than the clinically used anthelmintic drugs albendazole and ivermectin.5band5dkilled the total parasitic larvae (100% effectiveness) after 24 hours incubation period at 37 °C in both concentrations (50 and 100 μg ml?1). The antioxidant activity of the target compounds was elucidatedin vitroagainst stable free radicals DPPH and ABTS as well as iron induced oxidative damage in model systems containing biologically relevant molecules lecithin and deoxyribose. The two 2,3- and 3,4-dihydroxy hydrazones5band5dwere the most effective radical scavengers in all studied systems. DFT calculations were applied to calculate the reaction enthalpies in polar and nonpolar medium and estimate the preferred mechanism of antioxidant activity. The relative radical scavenging ability of compounds5a-lshowed a good correlation to the experimentally observed trends. It was found that the studied compounds are capable to react with various free radicals - ˙OCH3, ˙OOH and ˙OOCH3, through several possible reaction pathways - HAT in nonpolar medium, SPLET in polar medium and RAF in both media.
- Argirova, Maria A.,Georgieva, Miglena K.,Hristova-Avakumova, Nadya G.,Vuchev, Dimitar I.,Popova-Daskalova, Galya V.,Anichina, Kameliya K.,Yancheva, Denitsa Y.
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p. 39848 - 39868
(2021/12/31)
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- COMPOUNDS AS RAS INHIBITORS AND USE THEREOF
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A compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof is described, wherein the substituents are as defined herein. Pharmaceutical compositions comprising the same and method of using the same are also described.
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Paragraph 0197
(2019/04/11)
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- Novel fluorescent triazinobenzimidazole derivatives as probes for labelling human A1 and A2B adenosine receptor subtypes
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The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N1 (1,2) or N10 (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A1 and A2B AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 3 revealed a higher affinity to A1 and A2B ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs. Fluorescence confocal microscopy showed that compound 3 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre-incubation with the A1 AR and A2B AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 3 could represent a useful tool to investigate the expression pattern of both A1 and A2B ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells.
- Barresi, Elisabetta,Giacomelli, Chiara,Daniele, Simona,Tonazzini, Ilaria,Robello, Marco,Salerno, Silvia,Piano, Ilaria,Cosimelli, Barbara,Greco, Giovanni,Da Settimo, Federico,Martini, Claudia,Trincavelli, Maria Letizia,Taliani, Sabrina
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p. 5885 - 5895
(2018/11/23)
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- Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
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A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5- methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.
- Nakao, Syuhei,Mabuchi, Miyuki,Shimizu, Tadashi,Itoh, Yoshihiro,Takeuchi, Yuko,Ueda, Masahiro,Mizuno, Hiroaki,Shigi, Naoko,Ohshio, Ikumi,Jinguji, Kentaro,Ueda, Yuko,Yamamoto, Masatatsu,Furukawa, Tatsuhiko,Aoki, Shunji,Tsujikawa, Kazutake,Tanaka, Akito
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p. 1071 - 1074
(2014/03/21)
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- Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping
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By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC50 = 13.12 ± 1.03 μM). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC50 values of 7.46 ± 1.15 to 48.59 ± 3.46 μM, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV.
- Deng, Jing,Li, Ning,Liu, Hongchuan,Zuo, Zhili,Liew, Oi Wah,Xu, Weijun,Chen, Gang,Tong, Xiankun,Tang, Wei,Zhu, Jin,Zuo, Jianping,Jiang, Hualiang,Yang, Cai-Guang,Li, Jian,Zhu, Weiliang
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p. 6278 - 6293
(2012/09/07)
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- Anticonvulsant evaluation of some newer benzimidazole derivatives: Design and synthesis
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A series of new 2-[(1-substituted phenylethylidine) hydrazine]-N-phenyl-1H- benzo[d]imidazole-1-carbothioamides (4a-n) were designed and synthesized to have the pharmacophoric elements essential for anti-convulsant activity. The key step in the synthesis
- Bhrigu, Bhanupriya,Siddiqui, Nadeem,Pathak, Devender,Alam, M. Shamsher,Ali, Ruhi,Azad, Bishmillah
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experimental part
p. 53 - 62
(2012/03/27)
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- Synthesis and biological activity of 2-{2'-[4"-substituted phenyl]-2'-Methylthiazolidine-4-one-3-ylamino}-1H-benzo [d] imidazoles
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Reaction of 2-hydrazinobenzimidazole (3) with substituted acetophenones (4a-j) yielded Schiffs bases (5a-j) which on further reaction with thioglycollic acid in the presence of anhyd Zinc Chloride furnished the titled compounds thiazolidinone derivatives
- Sharma, Nidhi,Pathak, Devender
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p. 143 - 146
(2013/09/24)
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- Synthesis and biological activity of 2-{2'-[substituted phenyl]-2'-Methylthiazolidine-4-one-3-ylamino}-1H-benzo [d] imidazoles
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Reaction of 2-hydrazinobenzimidazole (3) with respective acetophenones (4a-j) yielded Schiff's bases (5a-j) which on further reaction with thioglycollic acid in the presence of anhyd zinc chloride furnished the titled compounds thiazolidinone derivatives
- Sharma, Nidhi,Pathak, Devender
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- Designing Structural Motifs for Clickamers: Exploiting the 1,2,3-Triazole Moiety to Generate Conformationally Restricted Molecular Architectures
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Noncovalent interactions, especially hydrogen-bonding interactions as well as electrostatic forces, confined within one macromolecule are the key to designing foldamers that adopt well-defined conformations in solution. In the context of significant recent activities in the area of triazole-connected foldamers, so-called clickamers, we present a fundamental study that compares various model compounds that bear adjacent N-, O-, or F-heteroatom substituents. The interplay of attractive and repulsive interactions leads to rotational constraints around the single bonds attached to both the 1- and 4-positions of the 1,2,3-triazole moiety and should therefore be able to induce well-defined conformational preferences in higher oligomers and polymers, that is, foldamers. Various compounds were synthesized and characterized with regard to their preferred conformations in all three aggregation statesa-that is, in the gas phase, in solution as well as in the solid statea-by employing DFT calculations, NMR spectroscopic experiments, and X-ray crystallography, respectively. On the basis of the thus-obtained general understanding of the conformational behavior of the individual connection motifs, heterostructures were prepared from different motifs without affecting their distinct folding characteristics. Therefore, this work provides a kind of foldamer construction kit, which should enable the design of various clickamers with specific shape and incorporated functionality. A foldamer construction kit: Various heterostructures "clicked" together by structure-directing triazole moieties were investigated with regard to their conformational behavior. Different heteroatoms (X; see graphic) can be used to bias the conformation around the N(1)- and C(4)-connecting single bonds of the triazoles based on tunable noncovalent interactions.
- Zornik, Denise,Meudtner, Robert M.,Ela Malah, Tamer,Thiele, Christina M.,Hecht, Stefan
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supporting information; experimental part
p. 1473 - 1484
(2011/04/15)
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- SUBSTITUTED BENZIMIDAZOLES AND THEIR USE FOR INDUCING APOPTOSIS
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The invention relates to compounds of formula (I), wherein R represents aryl or heteroaryl, X is a bond, a carbonyl group, a derivative of a carbonyl group, an ethylene group or an ethylenecarbonyl group, R1 is optionally substituted amino or hydroxy, and the substituents R2 to R6 have the meanings given in the specification, to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to intermediates, to the use of a compounds of formula (I) as a medicament and for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.
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(2010/02/13)
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- Synthesis and Antiviral Activity of Formazans and Their Tetrazolium Bromides Derived from Benzimidazol
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Sixteen new formazans (IV) have been synthesised by the coupling of aryldiazonium chlorides with 4-methoxy-3-nitrobenzaldehyde 2-benzimidazolylhydrazone (III).The formazans (IV) on oxidation with H2O2/Fe++ undergo cyclisation to give the corresponding tetrazolium chlorides which are converted into bromides (V) by treatment with excess of NaBr.Compound III has been prepared by the reaction of 2-hydrazinobenzimidazole (II) and 4-methoxy-3-nitrobenzaldehyde.Compound II in turn has been prepared by the action of hydrazine hydrate on 2-mercaptobenzimidazole.Thesecompounds (II-V) have been screened for their antiviral action against the plant viruses PVX and CGMMV both in vivo and in vitro and found to exhibit 38-63percent activity in vivo and 24-74percent in vitro.
- Srivastava, Neeru,Misra, V. S.
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p. 298 - 300
(2007/10/02)
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- Studies on Heterocyclic Compounds. Part VI: Synthesis of Bridgehead Nitrogen Triazine and Pyrimidine Heterocycles
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New bridgehead nitrogen containing heterocycles such as thiazolotriazine (IVa and IVb), imidazolotriazine (IVc), triazinotriazine (IVd and IVe) and oxadiazolotriazine (IVf) and several of their derivatives (V) have been prepared by reacting their respective hydrazine (II) with ethylpyruvate and phenyl glycoxalic acid.The diazotization of hydrazine (II) furnished the reactive intermediates (VI) (azido form) and (VII) (tetrazole form) depending on the structure of hydrazines.These intermediates have been used to synthesise bridgehead nitrogen pyrimidine derivatives (VIII) by reacting them with diethyl fumarate.The spectral and chemical evidences show that diazotised products obtained from 2-hydrazino-4-phenyl thiazole (IIa) and 2-hydrazino benzothiazole (IIb) exist in tetrazole form (VIIa) and (VIIb), respectively, whereas the remaining four (IIa-IIf) remain in the azido form (VIc-VIf) in the solid state.
- Dehuri, S. N.,Pradhan, P. C.,Nayak, A.
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p. 475 - 478
(2007/10/02)
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