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A series of 5-azaquinoxaline-2,3-dione derivatives were synthesized and evaluated on d-amino acid oxidase (DAAO) inhibition as potential alpha-hydroxylactam-based inhibitors. The potent inhibitory activities in vitro suggested that 5-nitrogen could significantly enhance the binding affinity by strengthening relevant hydrogen bond interactions. The analgesic effects of intrathecal and systemic injection of 8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione, a representative molecule of 5-azaquinoxaline-2,3-dione, were investigated in rodents. This research not only confirmed the analgesic effect of the DAAO inhibitors but provided a new class of chemical entities with oral application potential for the treatment of chronic pain and morphine analgesic tolerance.

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To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-alpha, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.

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2-Substituted pyrrolo[2,3-b]quinoxalines having free NH were prepared directly from 3-alkynyl-2-chloroquinoxalines in a single pot by using readily available and inexpensive methane sulfonamide (or p-toluene sulfonamide) as an ammonia surrogate. The reaction proceeded in the presence of Cu(OAc)2 affording the desired product in moderate yield. The crystal structure analysis of a representative compound and its supramolecular interactions are presented. Some of the compounds synthesized exhibited inhibitory activities against luciferase that was supported by the predictive binding mode of these compounds with luciferase enzyme through molecular docking studies. The key observations disclosed here can alert users of luciferase reporter gene assays for possible false positive results due to the direct inhibition of luciferase.

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2-Substituted 3-oxo-3,4-dihydroquinoxalines were oxidized with H2O2 to 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline.This oxidation of the imino bonding in the heterocycles to the lactam was assumed to proceed via the various peroxides, but not via the oxaziranes.

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New series of [1,2,4]triazolo [4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3?,4?-c]quinoxaline derivatives have been designed, synthesized and biologically evaluated for their cytotoxic activities against three tumor cell lines (HePG-2, Hep-2 and Caco-2). Compounds 16e, 21, 25a and 25b exhibited the highest activities against the examined cell lines with IC50 values ranging from 0.29 to 0.90 muM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 muM). The most active members were further evaluated for their topoisomerase II (Topo II) inhibitory activities and DNA intercalating affinities as potential mechanisms for their anti-proliferative activities. Interestingly, the results of Topo II inhibition and DNA binding assays were consistent with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited good Topo II inhibitory activities and DNA binding affinities, comparable to that of doxorubicin. Moreover, the most active compound 25a caused cell cycle arrest at G2/M phase and induced apoptosis in Caco-2 cells. In addition, Furthermore, molecular docking studies were performed for the novel compounds against DNA-Topo II complex to investigate their binding patterns. Based on these studies, it was concluded that DNA binding and/or Topo II inhibition may contribute to the observed cytotoxicity of the synthesized compounds.

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A novel series of quinoxalinediones possessing imidazolyl and related heteroaromatic substituents was synthesized and evaluated for their activity to inhibit [3H]AMPA binding from rat whole brain. From the structure- activity relationships, it was found that the 1H-imidazol-1-yl moiety could function as a bioisostere for the cyano and nitro groups, and that 6-(1H- imidazol-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (11) showed the most potent activity for the AMPA receptor. Compound 11 was evaluated for selectivity versus other excitatory amino acid receptors, and its action against AMPA at its receptor in the rat striatum was characterized. These data showed that compound 11 was a selective antagonist for the AMPA receptor with a K(i) value of 0.084 muM, being approximately equipotent with 2,3-dihydro-6-nitro- 7-sulfamoylbenzo(f)quinoxaline (3) (NBQX; K(i) = 0.060 muM). Compound 11 was also found to give protection against sound-induced seizure on DBA/2 mice at the minimum effective dose of 3 mg/kg ip (3; 10 mg/kg ip).

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The reaction of o-phenylene diamine and ethyl oxamate is reinvestigated and led to 3-aminoquinoxalin-2(1H)-one rather than benzimidazole-2-carboxamide as was previously reported. The structure of the obtained quinoxaline has been confirmed by X-ray. The anti-tumor activity of synthesized quinoxalines 1-21 has been evaluated by studying their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13- acetate (TPA). Among the studied compounds 1-21, compounds 12, 8, 13, 18, 17 and 19, respectively, demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 12 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The result of the present investigation indicated that compound 12 might be valuable as a potent cancer chemopreventive agent. Moreover, the molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.

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We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3- b]pyrazinedione derivatives 4, 7-10, 13, 15, and 16 showed some differences in comparison with those of the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that conformation of the 7-nitro group of 1 · HCl was nearly coplanar with the quinoxaline ring, whereas the 6- imidazol1-yl group was rotated with respect to the aromatic ring. From the glycine site on NMDA receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones may be responsible for the selectivity against the glycine site. Among the series of azaquinoxalinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3- b]pyrazinedione (8c) exhibited a combination of the best affinity to the AMPA receptors with a K(i) value of 0.14 muM and selectivity against the glycine site (no affinity at 10 muM). In vivo, 8c also protected against sound- induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).

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N-chlorinated sulphonic acids of the formula STR1 (wherein R is group STR2 and their salts, particularly their sodium and potassium salts, are disclosed. These compounds are chlorine release agents and may be used as bleaching or germicidal agents either alone or in cleansing or detergent compositions. Preferred compounds are those wherein R is a group STR3 in the form of their sodium or potassium salts.

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A series of quinoxalinone derivatives were synthesized by the reaction of o-phenylenediamine with oxalic acid to yield 1, 4-dihydro quinoxaline-2, 3-dione (1) and then treated with thionyl chloride to yield 2, 3 dichloro quinoxaline (2). This was further reacted with hydrazine hydrate to produce 2, 3-dihydrazinyl quinoxaline (3). This was finally reacted with substituted aromatic aldehydes to produce 2,3-bis[2-(sustituted benzylidine) hydrazinyl] quinoxalines (4). These quinoxalinone derivatives were characterized by infrared spectroscopy and nuclear magnetic resonance spectroscopy and MASS spectral data. All the synthesized compounds were evaluated for their antimicrobial activity. The results of the antimicrobial study revealed that compounds 4c, 4d, and 4i were active and exhibited better inhibitory activities as compared to standard drug ciprofloxacin. The results were further checked with protein legend interaction by using docking studies, and all the compounds exhibited good docking scores between ?8.72 and ?11.29 kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID-4XE6). Among all compound, 4c has shown maximum docking score and found in agreement to in vitro studies.

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