15804-19-0Relevant articles and documents
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Platt
, p. 439 (1946)
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Triazolo[4,3-a] quinoxaline and [1,2,4]triazolo[4,3- a] quinoxaline-1-thiol-derived DNA intercalators: Design, synthesis, molecular docking, in silico ADMET profiles and anti-proliferative evaluations
El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Elwan, Alaa
, p. 881 - 897 (2021)
In view of their DNA intercalation activities as anticancer agents, 17 novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 cells. Molecular docking studies were performed to investigate the binding modes of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with those obtained from the molecular modeling studies. MCF-7 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compound 12d was found to be the most potent derivative of all the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC50 = 22.08 ± 2.1, 27.13 ± 2.2 and 17.12 ± 1.5 μM, respectively. Although this compound displayed nearly one third of the activity of doxorubicin (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM, respectively), it may be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. Compounds 12a, 10c and 10d displayed very good anticancer activities against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC50 = 31.40 ± 2.8, 28.81 ± 2.4 and 19.72 ± 1.5 μM for 12a, 33.41 ± 2.9, 29.96 ± 2.5 and 24.78 ± 1.9 μM for 10c, and 37.55 ± 3.3, 30.22 ± 2.6 and 25.53 ± 2.0 μM for 10d. The most active derivatives, 10c, 10d, 10h, 12a, 12b and 12d, were evaluated for their DNA binding activities. Compound 12d displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (35.33 ± 1.8 μM), which is nearly equipotent to that of doxorubicin (31.27 ± 1.8 μM). Compounds 12a and 10c exhibited good DNA-binding affinities, with IC50 values of 39.35 ± 3.9 and 42.35 ± 3.9 μM, respectively. Finally, compounds 10d, 10h and 12b showed moderate DNA-binding affinities, with IC50 values of 50.35 ± 3.9, 57.08 ± 3.3 and 59.35 ± 3.2 μM, respectively.
Design, synthesis, molecular docking and anti-proliferative evaluations of [1,2,4]triazolo[4,3-a]quinoxaline derivatives as DNA intercalators and Topoisomerase II inhibitors
El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Elwan, Alaa
, (2020)
In view of their DNA intercalation activities as anticancer agents, novel twenty four [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 as DNA intercalators and Top II enzyme inhibitors. The data obtained from molecular modeling studies revealed that, our small aromatic molecules were concluded to act through two ways firstly, through non-covalent interaction with the directly bound proteins to DNA hence inhibit topoisomerase-II enzyme. The second is through non-covalently binding to double helical structures of DNA either by intercalating binder as in compounds 10a and 11d or by minor groove binding as in compounds 8e and 8c. Cytotoxic activity indicated that MCF-7 and HepG2 were the most sensitive cell lines to the influence of the new derivatives respectively. In particular, compounds 10a, 11d and 8e were found to be the most potent derivatives overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = (4.55 ± 0.3, 6.18 ± 0.8 and 3.93 ± 0.6 μM), (5.61 ± 0.5, 6.49 ± 0.5and 3.71 ± 0.3 μM) and (4.66 ± 0.3, 8.08 ± 0.8 and 5.11 ± 0.7 μM) respectively. The three derivatives exhibited higher activities than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM respectively), against HepG2 and MCF-7 but 8e exhibited nearly the same activity against HCT116 cancer cell lines respectively. The most active derivatives 8a-e, 10a,b, 11b-e, 13a and 14b,c were evaluated for their DNA binding activities. The tested compounds displayed very good to moderate DNA-binding affinities. Compounds 10a 11d, 8e, 8c, 8a and 8b displayed the highest binding affinities. These compounds potently intercalate DNA at decreased IC50 values of 25.27 ± 1.2, 27.47 ± 2.1, 27.54 ± 3.2, 27.78 ± 1.3, 29.15 ± 1.8 and 30.23 ± 3.7 μM respectively, which were less than that of doxorubicin (31.27 ± 1.8). Furthermore, the most active cytotoxic compounds 8a, 8b, 8c, 8e, 10a and 11d were selected to evaluate their inhibitory activities against Topo II enzyme. All the tested compounds could interfere with the Topo II activity. They exhibited very good inhibitory activities with IC50 values ranging from 0.379 ± 0.07 to 0.813 ± 0.14 μM that were lower than that of doxorubicin (IC50 = 0.94 ± 0.4 μM). For a great extent, the reported results were in agreement with that of in vitro cytotoxicity activity, DNA binding and molecular modeling studies.
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Lane
, p. 1079 (1955)
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Ishikawa,Shin-ya
, p. 673,674 (1976)
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Studies in the heterocyclic series. XVII: A new type of triazaphenothiazine heterocycle
Okafor
, p. 149 - 153 (1980)
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Ytterbium triflate catalyzed heterocyclization of 1,2-phenylenediamines and alkyl oxalates under solvent-free conditions via phillips reaction: A facile synthesis of quinoxaline-2,3-diones derivatives
Wang, Limin,Liu, Jijun,Tian, He,Qian, Changtao
, p. 1349 - 1357 (2004)
Ytterbium triflate are found to catalyze efficiently the Phillips-type heterocyclization reactions of 1,2-phenylenediamine and alkyl oxalate under solvent-free and mild conditions to afford the corresponding quinoxaline-2,3-dione derivatives in high yields. The catalyst could be recovered almost quantitatively from the aqueous layer after the reaction was completed and it could be reused in subsequent reaction without decrease in activity.
Facile synthesis and anti-proliferative activity evaluation of quinoxaline derivatives
Li, Zhulai,Lin, Jin,Wang, Jian,Wang, Panpan,Xu, Xiuzhi,Xue, Guozhen,Zha, Daijun,Zhang, Zemin
, (2020)
A series of “drug-like” compounds based on quinoxaline scaffold with arylsulfonyl hydrazinyl, arylformyl hydrazinyl or arylsulfonyl groups at C-2 and aryloxy groups at C-3, were synthesized in 4 or 5 steps involving cyclization, chlorination and coupling reactions. Cellular anti-proliferative activities of these quinoxaline derivatives in vitro were determined, which revealed that the inhibitory potency and selectivity of 6f was comparable to that of the positive control.
Synthesis of Novel Substituted Phenyl-3-Hydrazinyl-Quinoxaline-2-Amine Derivatives: Evaluation of Antimicrobial Activity and Its Molecular Docking Studies
Paliwal, Sarvesh,Sharma, Swapnil,Dwivedi, Jaya,Mishra, Achal
, p. 3689 - 3695 (2017)
New series of quinoxaline derivatives (4a–4h) were synthesized by treating 2-chloro-3-hydrazinyl quinoxalin (3) with various anilines. Compound 3 was obtained from the 2,3-dichloroquinoxaline 2 which was prepared from 4-dihydroquinoxaline-2,3-dione (1). All synthesized compounds (4a–4h) were characterized by various spectral techniques, that is, IR, 1H-NMR, mass spectroscopy, and elemental analysis and completion of reaction were confirmed by TLC. In vitro antimicrobial activity of synthesized compounds was evaluated using disc diffusion assay against gram-positive and gram-negative microbial strains, and then, the minimum inhibitory concentration and IC50 values of compounds were also determined. The results of antimicrobial study revealed that compounds 4e, 4g, and 4a were active and exhibited better inhibitory activities as compared with standard drug amoxicillin. Docking studies were performed by using Argus lab, and all the compounds exhibited good docking scores between ?9.53 and ?7.94?kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID-4XE6). Among all compounds, 4e has shown the maximum docking score and found in agreement to in vitro studies.
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Postovskii,I.Ya.,Koshel,N.G.
, (1971)
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Campaigne,van Verth
, p. 1344,1345 (1958)
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Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents
Shen, Qing-Kun,Gong, Guo-Hua,Li, Gao-,Jin, Mei-,Cao, Li-Hua,Quan, Zhe-Shan
, p. 85 - 95 (2020)
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-α, 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.
Theoretical and experimental investigation of acidity of the glutamate receptor antagonist 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding
De Freitas, Gutto R.S.,Coelho, Sara E.,Monteiro, Norberto K.V.,Neri, Jannyely Moreira,Cavalcanti, Lívia Nunes,Domingos, Josiel B.,Vieira, Davi S.,De Souza, Miguel A.F.,Menezes, Fabrício G.
, p. 7414 - 7423 (2017)
The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV-vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1′ binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host-guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2.
PHOTOCHEMICAL REACTIONS OF BIOLOGICALLY IMPORTANT QUINOXALINE N-OXIDES
Dvoryantseva, G. G.,Tetenchuk, K. P.,Pol'shakov, V. I.,Elina, A. S.
, p. 227 - 235 (1986)
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Koksharova,T.G. et al.
, (1977)
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Water superstructures within organic arrays; hydrogen-bonded water sheets, chains and clusters
Oxtoby, Neil S.,Blake, Alexander J.,Champness, Neil R.,Wilson, Claire
, p. 4643 - 4654 (2005)
A strategy for encouraging the formation of extended water arrays is presented, in which molecules that contain a 1,4-dihydroquinoxaline-2,3-dione core are used as supramolecular hosts for the accommodation of guest water molecules and arrays. These molecules were selected as they contain a hydrophilic oxalamide-based "terminus" that allows water molecules to hydrogen-bond to the host organic molecules as well as to each other. The host molecules also contain a hydrophobic "end" based upon an aromatic ring, which serves to encourage the formation of discrete water clusters in preference to three-dimensional networks, as the water molecules cannot form strong hydrogen bonds with this part of the molecule. A systematic study of several hydrated structures of four organic molecules based on 1,4-dihydroquinoxaline-2,3-dione (qd) is discussed. The organic molecules, qd, 6-methyl-1,4-dihydroquinoxaline-2,3-dione (mqd), 6,7-dimethyl-1,4- dihydroquinoxaline-2,3-dione (dmqd) and 1,4-dihydrobenzo[g]-quinoxaline-2,3- dione (Phqd), act as supramolecular crystal hosts for the clusters of water, with zero-, one- and two-dimensional arrays of water being observed. The hydrogen bonding in the structures, both within the water clusters and between the clusters and organic molecules, is examined. In particular, the structure of dmqd·6H2O contains a two-dimensional water sheet composed of pentagonal and octagonal units. Phqd·3H2O forms a hydrophilic extended structure encouraging the formation of one-dimensional chains consisting entirely of water. Both qd·2H2O and dmqd·2H2O can be considered to form one-dimensional chains, but only by utilising bridging carbonyl groups of the oxalamide moieties to form the extended array; if only the water is considered, zero-dimensional water tetramers are observed. The remaining hydrated structures, [Na+ dmqd-]dmqd·H2O, dmqd·1/3H2O and mqd·1/2H2O, all contain discrete water molecules but do not form extended water structures.
A new small molecule inhibitor of soluble guanylate cyclase
Mota, Filipa,Gane, Paul,Hampden-Smith, Kathryn,Allerston, Charles K.,Garthwaite, John,Selwood, David L.
, p. 5303 - 5310 (2015)
Soluble guanylate cyclase (sGC) is a haem containing enzyme that regulates cardiovascular homeostasis and multiple mechanisms in the central and peripheral nervous system. Commonly used inhibitors of sGC activity act through oxidation of the haem moiety, however they also bind haemoglobin and this limits their bioavailability for in vivo studies. We have discovered a new class of small molecule inhibitors of sGC and have characterised a compound designated D12 (compound 10) which binds to the catalytic domain of the enzyme with a KD of 11 μM in a SPR assay.
Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects
Alswah, Mohamed,Bayoumi, Ashraf H.,Elgamal, Kamal,Elmorsy, Ahmed,Ihmaid, Saleh,Ahmed, Hany E. A.
, (2018)
A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b–c, and 7e–g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 μM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a–c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 μM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets.
Evaluation of quinoxaline compounds as ligands of a site adjacent to S2 (AS2) of cruzain
Fabian,Martini, M. Florencia,Sarduy, Emir Salas,Estrin, Darío A.,Moglioni, Albertina G.
, p. 2197 - 2202 (2019)
The binding of ten quinoxaline compounds (1–10) to a site adjacent to S2 (AS2) of cruzain (CRZ) was evaluated by a protocol that include a first analysis through docking experiments followed by a second analysis using the Molecular Mechanics-Poisson-Boltzmann Surface Area method (MM-PBSA). Through them we demonstrated that quinoxaline compounds bearing substituents of different sizes at positions 3 or 4 of the heterocyclic ring might interact with the AS2, particularly interesting site for drug design. These compounds showed docking scores (ΔGdock) which were similar to those estimated for inhibitors that bind to the enzyme through non-covalent interactions. Nevertheless, the free binding energies (ΔG) values estimated by MM-PBSA indicated that the derivatives 8–10, which bear bulky substituents at position 3 of the heterocycle ring, became detached from the binding site under a dynamic study. Surprisingly, the evaluation of the inhibitory activity of cruzipain (CZ) of some derivatives showed that they increase the enzymatic activity. These results lead us to conclude about the relevance of AS2 as a pocket for compounds binding site, but not necessarily for the design of anti-chagasic compounds.
First coordination polymer of 1,4-dihydro-2,3-quinoxalinedione in ketoamine tautomeric form
Shi, Ling,Cai, Bin,Huang, Guang,Wu, Jian-Zhong,Yu, Ying
, p. 306 - 311 (2011)
The first coordination compound of 1,4-dihydro-2,3-quinoxalinedione in ketoamine tautomeric form (denoted as H2qdione) was reported. H 2qdione was obtained by a solid-state reaction of o-phenylenediamine and oxalic acid. Reaction of this ligand with CdCl2 solvothermally yielded a coordination polymer [Cd(H2qdione)Cl2] n, which was structurally characterized by X-ray diffraction and IR spectroscopy. Continuous Cd2Cl2 diamonds form a double-sided comb with terminal H2qdione-κ2O,O' as the comb teeth. Interaction of these combs through very extensive π-π stacking, C-HA...Cl, and N-HA...Cl hydrogen bonds leads to a novel 3D architecture and significant enhancement of solid-state luminescence of about 10 times compared to the free H2qdione ligand.
New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis
Alsaif, Nawaf A.,Dahab, Mohammed A.,Alanazi, Mohammed M.,Obaidullah, Ahmad J.,Al-Mehizia, Abdulrahman A.,Alanazi, Manal M.,Aldawas, Saleh,Mahdy, Hazem A.,Elkady, Hazem
, (2021)
New series of [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized, and biologically assessed for their anti-proliferative activities against two selected tumor cell lines MCF-7 and HepG2. Comparing to sorafenib (IC50 = 2.17 ± 0.13 and 3.51 ± 0.21 μM against MCF-7 and HepG2, respectively), compound 25d, 25e, 25i, and 27e exhibited the highest activities against the examined cell lines with IC50 values extending from 4.1 ± 0.4 to 11.7 ± 1.1 μM. Furthermore, VEGFR-2 inhibitory activities were assessed for all the synthesized compounds as potential mechanisms for their anti-proliferative activities. Compounds 25d, 25e, 25i, and 27e displayed prominent inhibitory efficiency versus VEGFR-2 kinase with IC50 value ranging from 3.4 ± 0.3 to 6.8 ± 0.5 nM. Fascinatingly, the results of VEGFR-2 inhibitory assays were matched with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited promising VEGFR-2 inhibitory activities. Further studies displayed the ability of compound 25d to induce apoptosis in HepG2 cells and can arrest the growth of such cells at the G2/M phase. Also, compound 25d produced a significant increase in the level of BAX/Bcl-2 ratio (3.8-fold), caspase- 3 (1.8-fold), and caspase-9 (1.9-fold) compared to the control cells. Molecular docking studies were carried out to investigate the possible binding interaction inside the active site of the VEGFR-2.
Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors
Abdallah, Abdallah E.,Abo-Saif, Mariam A.,Al Ward, Maged Mohammed Saleh,Alesawy, Mohamed S.,Eissa, Sally I.,El-Feky, Ola A.,El-Zahabi, Mohamed Ayman,Elkaeed, Eslam B.,Mabrouk, Reda R.,Mehany, Ahmed B. M.
, p. 573 - 591 (2022/01/20)
Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 μM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 μM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.
Choline Chloride-based Eutectic Mixtures for Greener Synthesis of Quinoxaline-2,3-diol Derivatives and Terephthalaldehyde bis-(2-Aminophenylimine)
Aghapoor, Kioumars,Darabi, Hossein Reza,Mohsenzadeh, Farshid,Sayahi, Hani
, (2021/12/29)
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Novel molecular targeting anti-tumor aza-steroid derivative based on lipid toxicity and preparation and application thereof
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Paragraph 0178; 0180; 0181; 0192; 0221, (2021/08/19)
The invention provides a novel molecular targeting anti-tumor aza-steroid derivative based on lipid toxicity and a preparation method and application thereof, and belongs to the field of chemical medicines. The derivative is a compound as shown in a formula I, or a salt thereof, or a stereoisomer thereof. The compound is low in toxicity or basically non-toxic to normal cells, has an obvious inhibition effect to tumor cell lines, particularly has good lipid toxicity selectivity to tumor cells such as liver cancer, lung cancer and the like in vivo, and has an obvious inhibition effect; meanwhile, the compound can effectively activate SREBP1 and PPAR gamma, inhibit lipid transport MTTP, cause lipid aggregation in tumor cells and cause lipid toxicity of the tumor cells. The compound can be used for treating liver cancer, lung cancer and the like in a molecular targeting manner, is low in toxicity or even non-toxic, and has a good application prospect.
