- Synthesis and reactivity of pyrrolo[1,2-a]quinoxalines. Crystal structure and AM1 calculation
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2-Methylquinoxaline reacts with ethyl bromopyruvate giving 2-substituted pyrrolo[1,2-a]quinoxalines. The yield of the condensation depends on the functionalization of starting materials, and optimization is obtained with 2-dimethylamino-3-methylquinoxalin
- Blache,Gueiffier,Ethakmaoui,Viols,Chapat,Chavignon,Teulade,Grassy,Dauphin,Carpy
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- Antiplasmodial 2-thiophenoxy-3-trichloromethyl quinoxalines target the apicoplast of Plasmodium falciparum
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The identification of a plant-like Achille's Heel relict, i.e. the apicoplast, that is essential for Plasmodium spp., the causative agent of malaria lead to an attractive drug target for new antimalarials with original mechanism of action. Although it is not photosynthetic, the apicoplast retains several anabolic pathways that are indispensable for the parasite. Based on previously identified antiplasmodial hit-molecules belonging to the 2-trichloromethylquinazoline and 3-trichloromethylquinoxaline series, we report herein an antiplasmodial Structure-Activity Relationships (SAR) study at position two of the quinoxaline ring of 16 newly synthesized compounds. Evaluation of their activity toward the multi-resistant K1 Plasmodium falciparum strain and cytotoxicity on the human hepatocyte HepG2 cell line revealed a hit compound (3k) with a PfK1 EC50 value of 0.3 μM and a HepG2 CC50 value of 56.0 μM (selectivity index = 175). Moreover, hit-compound 3k was not cytotoxic on VERO or CHO cell lines and was not genotoxic in the in vitro comet assay. Activity cliffs were observed when the trichloromethyl group was replaced by CH3, CF3 or H, showing that this group played a key role in the antiplasmodial activity. Biological investigations performed to determine the target and mechanism of action of the compound 3k strongly suggest that the apicoplast is the putative target as showed by severe alteration of apicoplaste biogenesis and delayed death response. Considering that there are very few molecules that affect the Plasmodium apicoplast, our work provides, for the first time, evidence of the biological target of trichloromethylated derivatives.
- Amanzougaghene, Nadia,Amrane, Dyhia,Azas, Nadine,Azqueta, Amaya,Mazier, Dominique,Primas, Nicolas,Sanz-Serrano, Julen,Tajeri, Shahin,Vanelle, Patrice,Verhaeghe, Pierre,Arnold, Christophe-Sébastien,Botté, Cyrille,Hutter, Sébastien,Louis, Béatrice
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- Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline
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Monoxide and dioxide of animo quinoxaline were synthesized and characterized by 1H NMR, 13C NMR and HRMS. The result shows that monoxide is main product. 1H NMR analysis, quantum calculation and crystal structure all indicate that the monoxide is 4-oxide structure but not 1-oxide structure. The subsequent discussions of electronic effect and steric effect of 1-oxide and 4-oxide support the conclusion that 4-oxide is dominant product, which is consistent with 1H NMR analysis and crystal structure. At last, the calculated structure is in good agreement with the crystal structure in this paper, which indicates that the calculation result in this paper is credible.
- Li, Junjian,Wang, Rui,Wang, Wenfeng,Wang, Xucheng,Yuan, Yaofeng,Zhang, Min
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- Design and synthesis of new quinoxaline derivatives as anticancer agents and apoptotic inducers
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The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.
- El Newahie, Aliya M.S.,Nissan, Yassin M.,Ismail, Nasser S.M.,Abou El Ella, Dalal A.,Khojah, Sohair M.,Abouzid, Khaled A.M.
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- Method for preparing ethylene glycol compounds
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The invention provides a method for preparing ethylene glycol compounds. The preparation method is short in route, the yield is high, and the operation is simple, Compounds VIII and IX serve as intermediates for preparing the ethylene glycol compounds in the invention, and the ethylene glycol compounds disclosed by the invention are prepared by taking the compounds VIII and IX as the intermediates. The method is high in yield, high in purity and suitable for industrial production.
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- Inexpensive Radical Methylation and Related Alkylations of Heteroarenes
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A simple method for the introduction of a methyl and higher aliphatic group to various heteroarenes using very inexpensive reagents is described. It is based on the radical addition of a carboxylic xanthate followed by decarboxylation. Depending on the heteroarene structure, the decarboxylation can be spontaneous or induced by heating in N,N-dimethylacetamide or N-methyl pyrrolidone in a microwave oven.
- Huang, Qi,Zard, Samir Z.
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supporting information
p. 1413 - 1416
(2018/03/09)
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- DNA topoisomerase II inhibition has the activity of modulating kui analogue and its preparation method and application
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The invention discloses a quinoxalinone analog with DNA (deoxyribonucleic acid) topoismerase II inhibiting activity, an optical isomer, diastereoisomer or racemic mixture, or pharmaceutically acceptable salt, solvate, prodrug, intermediate or metabolite thereof. The structural general formula is disclosed as Formula (I), wherein R1, R2, R3, R4, R5 and Ar are defined in the specification. The invention also discloses a preparation method of the compounds and application of the compounds as drugs and in treating tumors. The compounds have the advantages of definite curative effect and small toxic and side effects, enriches the varieties of inhibitors of drugs for treating diseases caused by topoismerase II expression abnormity in the prior art, and is hopeful to become clinical drugs with higher therapeutic index.
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- A new solvent for the reaction of chlorination of hydroxyquinoxaline derivatives with vilsmeier reagent
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A new efficient procedure for the chlorination of hydroxyquinoxaline derivatives into the corresponding chlorides is described. It has been found that the use of 1-chlorobutane produces the highest yield, reduces the time of reaction and facilitates direct formation of crystals without any purification.
- Bouanane, Zohra,Bounekhel, Mahmoud,Elkolli, Meriem,Takfaoui, Abdelilah
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p. 903 - 906
(2018/04/09)
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- A novel method for heterocyclic amide-thioamide transformations
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In this paper, we introduce a novel and convenient method for the transformation of heterocyclic amides into heteocyclic thioamides. A two-step approach was applied for this transformation: Firstly, we applied a chlorination of the heterocyclic amides to afford the corresponding chloroheterocycles. Secondly, the chloroherocycles and N-cyclohexyl dithiocarbamate cyclohexylammonium salt were heated in chloroform for 12 h at 61°C to afford heteocyclic thioamides in excellent yields.
- Fathalla, Walid,Ali, Ibrahim A. I.,Pazdera, Pavel
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supporting information
p. 174 - 181
(2017/02/15)
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- Design, synthesis, biological evaluation and molecular docking study on peptidomimetic analogues of XK469
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XK469 is identified as a potent quinoxaline antineoplastic agent based on its significant clinical efficacy. It probably exerts its activity via DNA topoisomerase II (topo II) inhibition. To obtain more effective antineoplastic agents, a spectrum of peptidomimetic-type quinoxaline analogues of XK469 was herein designed, synthesized, and evaluated. Few compounds (e.g. 13a and 13b) exhibited obvious cytotoxicity indicated by in?vitro anti-proliferative assay. SAR investigation revealed that introducing of hydrophobic tert-butylamine or dodecylamine moiety at the 3-position of quinoxaline core is favorable for achieving a better anti-proliferative potency, while peptidomimetic derivatives only yielded moderate cytotoxicity. Compounds with improved anti-proliferative activities also demonstrated decent anti-metastatic potencies comparable with that of doxorubicin (Doxo) based on in?vivo mouse model study. The topo II-mediated kinetoplast DNA (kDNA) decatenation assay as well as molecular docking studies implicated that these compounds tend to be potent topo II inhibitors. Overall, compounds 13a and 13b, 13b in particular, standed out from various assessments and might be promising candidates for further chemical optimization.
- Xia, Qiao-Hong,Hu, Wei,Li, Chen,Wu, Ji-Feng,Yang, Liang,Han, Xue-Mei,Shen, Yue-Mao,Li, Zhi-Yu,Li, Xun
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p. 311 - 325
(2016/09/07)
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- TRIAZOLOPYRAZINE DERIVATIVES AND THEIR USE FOR TREATING NEUROLOGICAL AND PSYCHIATRIC DISORDERS
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The present invention is directed to triazolopyrazine compounds of Formula (I). Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds as therapeutic agents treating neurological and psychiatric disorders.
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- Facile and efficient regioselective synthesis of 1-(3′-substituted quinoxalin-2′-yl)-3-aryl/heteroaryl-5-methylpyrazoles
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This report describes an efficient and practical approach for regioselective synthesis of 1-(3′-substituted quinoxalin-2′-yl)-3- aryl/heteroaryl-5-methylpyrazoles (3a-j). Reaction of 2-chloro-3-substituted quinoxalines (1) with 3(5)-methyl-5(3)-aryl-1H-pyrazoles (2) in the presence of sodium hydride furnished the title compounds in excellent yields with good levels of regioselectivity. The present protocol is superior to the existing method, which yielded a mixture of regioisomeric pyrazoles (I, II) and triazolo[4,3-a]quinoxalines (III). Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Aggarwal, Ranjana,Masan, Eakta,Sumran, Garima
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p. 1842 - 1848
(2013/05/21)
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- Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a] quinoxaline derivatives as inhibitors of the human protein kinase CK2
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Herein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxaline-carboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using
- Guillon, Jean,Le Borgne, Marc,Rimbault, Charlotte,Moreau, Stéphane,Savrimoutou, Solène,Pinaud, No?l,Baratin, Sophie,Marchivie, Mathieu,Roche, Séverine,Bollacke, Andre,Pecci, Adali,Alvarez, Lautaro,Desplat, Vanessa,Jose, Joachim
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p. 205 - 222
(2013/10/01)
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- Synthesis of triazoloquinoxalines as antitubercular agents
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1,2,4-Triazoles and quinoxalines were found to display various pharmacological activities. Hence a series of 1- aryl-4-methyl-1,2,4-triazolo[4, 3-a]quinoxalines were synthesized. Due to various advantages of organic reactions under solvent-free conditions these compounds were developed using iodobenzene diacetate under solvent-free conditions. The synthesized compounds were characterized by elemental microanalysis, infrared spectroscopy, 1H NMR, 13C NMR and HRMS. All the synthesized compounds were investigated for their antitubercular activity and 5g was found to the most active compound.
- Sekhar, Kondapalli Venkata Gowri Chandra,Rao, Vajja Sambasiva,Kumar, Dalip
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p. 2657 - 2660
(2012/01/05)
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- Synthesis and antimicrobial activity of some new thioether derivatives of quinoxaline
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2-Chloro-3-methylquinoxaline was selected as nucleus around which the molecular manipulations were carried out to get new compounds expected to possess better anti microbial activity. Various quinoxaline derivatives have been synthesized by replacing the chlorine at C-2 with a thioether linkage, which in turn attached to 2-(N-(substituted phenyl)acetamides. The synthesized compounds (5) were tested for their antimicrobial activity. Compounds 5b, 5c, 5d and 5i were found most active (comparable to the standard antibacterial Ciprofloxacin) amongst them. The structure of the compounds was confirmed on the basis of their spectral data.
- Singh,Hashim,Singhal
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p. 635 - 642
(2012/02/15)
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- Synthesis of some new 4-styryltetrazolo[1,5-a]quinoxaline and 1-substituted-4-styryl[1,2,4]triazolo[4,3-a]quinoxaline derivatives as potent anticonvulsants
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4-Methyltetrazolo[1,5-a]quinoxaline (3) was prepared by the azide cyclocondensation of 2-chloro-3-methylquinoxaline (2). The reaction of 3 with aromatic aldehydes furnished 4-styryltetrazolo[1,5-a]quinoxalines (4a-f). Compound 2, on treatment with hydrazi
- Wagle, Shivananda,Adhikari, Airody Vasudeva,Kumari, Nalilu Suchetha
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experimental part
p. 1135 - 1143
(2009/09/27)
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- Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo
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Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H 4 receptor (H4R) from which 2-(4-methyl-piperazin-l-yl)- quinoxaline (3) was identified as a new lead structure for H4R ligands. Exploration of the structure-activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-l-yl) quinoxalin-2(1H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-l-yl) quinoxaline (VUF 10148, 20) as potent H4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.
- Smits, Rogier A.,Lim, Herman D.,Hanzer, Agnes,Zuiderveld, Obbe P.,Guaita, Elena,Adami, Maristella,Coruzzi, Gabriella,Leurs, Rob,De Esch, Iwan J. P.
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p. 2457 - 2467
(2008/12/22)
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- Synthesis and anti microbial activity of quinoxaline based thiazolidinones and azetidinones
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Several 2-aryl-3- (3′methyl quinoxalin-2′-yl-amino) 4-thiazolidinoes 6a-l and 1-N-(3′methylquinoxalin-2′-yl-amino)4-aryl -3-chlodro-2-azetidinones 7a-l have been synthesized and tested for their antimicrobial and antifungal activity against different microorganism. The structure of compounds 6a-l and 7a-l have been conformed on the basis of their elemental and spectral data.
- Vyas,Chauhan,Parikh
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p. 1699 - 1702
(2008/09/19)
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- Pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one: Synthesis and characterization of a novel tetracyclic ring system
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(Chemical Equation Presented) Derivatives of the hitherto unknown ring system, pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one, are synthesized in one step from the corresponding 1-substuituted or 1,3-disubstituted 2-pyrazolin-5-ones and 3-chloroquinoxaline-2-carbonyl chloride using calcium hydroxide in boiling 1,4-dioxane. The parent system carrying no substituent in positions 1 and 3 is obtained upon treatment of the 1-PMB (p-methoxybenzyl) protected congener with trifluoroacetic acid. Detailed NMR spectroscopic investigations including unambiguous chemical shift assignments of all 1H, 13C, and 15N resonances of the obtained tetracycles are reported.
- Eller, Gernot A.,Datterl, Barbara,Holzer, Wolfgang
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p. 1139 - 1143
(2008/04/12)
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- Synthesis and antimicrobial activity of 2-substituted benzyl hydrazino-3-methyl quinoxalines
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Reduction of 3-methyl-2-(arylidcne hydrazino)quinoxalines 5a-1 with NaBH4 in controlled experimental conditions to give the 2-substituted benzyl hydrazine-3-methyl quinoxalines 6a-l have been described. The structure of compounds 6a-l have been confirmed from elemental analysis, IR, 1H NMR and mass spectral data. All the compounds have been screened for their antimicrobial activity against several microbes.
- Vyas,Chauhan,Parikh
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p. 972 - 974
(2007/10/03)
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- Studies on the synthesis of 2-phenylsulphonyl-3-styrylquinoxalines
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o-Phenylenediamine 1 is condensed with pyruvic acid or sodium pyruvate to yield 3-methylbenzo-1H-dihydropyrazine-2-one 2. The latter on condensation with aromatic aldehydes give 3-styrylquinoxaline-1H-2-one 3. Reaction of 3 with POCl3 in the presence of catalytic amount of DMF yields 2-chloro-3-styrylquinoxaline 4, which on reaction with thiophenol in the presence of triethylamine in methanol gives 2-phenylthio-3-styrylquinoxaline 5. Oxidation of 5 with H2O2 in the presence of acetic anhydride affords 2-phenylsulphonyl-3-styrylquinoxaline 6. 6 has also been prepared directly from 4 by reaction with sodium benzenesulphinate under phase transfer conditions. In an alternate approach to the synthesis of title compound. 2 is treated with POCl3 in DMF to obtain the known 2-chloro-3-methylquinoxaline 7. Reaction of 7 with thiophenol in the presence of triethylamine in methanol gives 2-methyl-3-phenylthioquinoxaline 8. Oxidation of 8 with H2O2 in Ac2O affords 2-methyl-3-phenylsulphonylquinoxaline 9. 9 was also prepared in an alternate method from 7 by reaction with sodium benzenesulphinate, 9 on reaction with aromatic aldehydes yields the title compounds 6.
- Krishnan,Chowdary,Dubey,Vijaya
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p. 565 - 573
(2007/10/03)
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- A FACILE SYNTHESIS OF NOVEL TRICYCLIC COMPOUNDS, TETRAZOLOQUINOXALINES AND 1,2,4-TRIAZOLOQUINOXALINES
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Novel 5-methyltetrazoloquinoxalin-4-ones (5) and 5-methyl-1,2,4-triazoloquinoxalin-4-ones (7) could be synthesized from 1-methyl-3-chloroquinoxalin-2-ones (3) and 1-methyl-3-hydrazinoquinoxalin-2-ones (6), respectively.Further extensive study was carried out to synthesize 4- or 7- substituted and 4,7-disubstituted tetrazoloquinoxalines (10) and 1,2,4-triazoloquinoxalines (12).
- Makino, Kenzi,Sakata, Gozyo,Morimoto, Katsushi
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p. 2025 - 2034
(2007/10/02)
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