- Determinants of activity at human toll-like receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of diverse heterocyclic scaffolds
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Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing heuristics to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.
- Yoo, Euna,Salunke, Deepak B.,Sil, Diptesh,Guo, Xiaoqiang,Salyer, Alex C. D.,Hermanson, Alec R.,Kumar, Manoj,Malladi, Subbalakshmi S.,Balakrishna, Rajalakshmi,Thompson, Ward H.,Tanji, Hiromi,Ohto, Umeharu,Shimizu, Toshiyuki,David, Sunil A.
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- Functionalization of gold nanoparticles with two aminoalcohol-based quinoxaline derivatives for targeting phosphoinositide 3-kinases (PI3Kα)
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Quinoxaline derivatives have attracted considerable attention due to their vast range of applications that includes electroluminescence and biomedicine. Concerning the latter, the literature has shown that compounds with a quinoxaline motif bind quite efficiently to phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks), which are enzymes found to be overexpressed in some types of neoplasms. In the present study, gold nanoparticles (AuNPs) were easily functionalized with 2,3-diethanolminoquinoxaline (DEQX) and 2-(2,3-dihydro-[1,4]oxazino[2,3-b]quinoxalin-4-yl)ethanol (OAQX). We made use of glycerol in alkaline media as reducing agent and the quinoxalines served as capping ligands to stabilize the AuNPs. This is the first report on the modification of a nanostructure with quinoxalines. Functionalization confers nanoparticles the required specificity to target only cancer cells, which opens possibilities for phototherapy since the modified AuNPs would concentrate in the tumor tissue as a consequence of PI3Kα overexpression. Molecular dynamics simulations have shown that DEQX and OAQX are potential inhibitors of PI3Kα since they bind to the active site of the enzyme in a way similar to other known inhibitors.
- Araújo, Janine,Menezes, Fabrício G.,Silva, Heloiza F. O.,Vieira, Davi S.,Silva, Sergio R. B.,Bortoluzzi, Adailton J.,Sant'Anna, Celso,Eugenio, Mateus,Neri, Jannyely M.,Gasparotto, Luiz H. S.
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- Synthesis, structural, catecholase, tyrosinase and DFT studies of pyrazoloquinoxaline derivatives
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Six functional multidentate ligands: 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl) quinoxaline, L1, 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-nitroquinoxaline, L2, 2,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylquinoxaline, L3, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydrazinyl-6-nitroquinoxaline L4, 2-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylquinoxaline, L5, 2-chloro-3-(3,5-dimethyl-1H-pyrazol-1-yl) quinoxaline, L6, and a new copper (II) complex, were prepared and evaluated for their catecholase activities at aerobic conditions. We found that, the reaction rate depends on: The nature of the substituents in the quinoxaline ring, counter anion, metal, concentration of ligand and the used solvent. The complex obtained in-situ from reaction of one equivalent of ligand L1 and two equivalents of Cu(CH3COO)2 in methanol showed the highest oxidation rate activity (V?=?33.48?μmol?L?1. min?1). In addition, geometry optimizations of the complexes in order to get better insight into the geometry and the electronic structure and chemical reactivity were carried out by means of DFT calculations.
- Bouanane, Zohra,Bounekhel, Mahmoud,Elkolli, Meriem,Abrigach, Farid,Khoutoul, Mohamed,Bouyala, Rabab,Touzani, Rachid,Hellal, Abdelkader
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- One-pot synthesis of novel substituted quinoxaline piperazine derivatives and their antimicrobial activities
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The present investigation reports the preparation of 1-(4-(tolyl quinoxaline-2-yl) piperazine-1-yl) derivatives catalyzed via polymer supported reagents. We have developed novel quinoxaline piperazine derivatives from 2,3-dichloroquinoxaline, wherein one chloro group is substituted with an aryl group, and the other is substituted by alkyl and aryl piperazine derivatives, through aromatic nucleophilic substitution reaction, and Suzuki coupling reactions to substituted quinoxaline-piperazine derivatives (5a-5g) compounds. The synthesized compounds were identified using FTIR, 1H NMR, 13C NMR and LC-MS. The synthesized compounds were examined for their antimicrobial activity. The results indicated that 5d, 5f and 5 g compounds have exhibited well to moderate antibacterial activity with the zone of inhibition of 18, 22 and 21 mm for Escherichia coli (40 μg/mL), and 17, 19 and 17 mm for Staphylococcus aureus (40 μg/mL). Besides, 5f compound showed respectable results to moderate antifungal activity with the zone of inhibition of 21 mm for Aspergillus niger (40 μg/mL) and 19 mm for Candida albicans (40 μg/mL). The established synthetic route is beneficial to develop various key intermediates as well as active pharmaceutical ingredients for pharmaceutical applications.
- Abdel-Hafez, Shams H.,Fahmy, Heba Mohamed,Hessien, Mahmoud M.,Narasimha Reddy, Y.,Reddy G, Nagaraja,Reddy Mardi, Radhakrishna,Reddy T, Sreenivasulu,Seku, Kondaiah,Shalan, Ahmed Esmail
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- Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors
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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.
- 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.
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p. 573 - 591
(2022/01/20)
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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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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.
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Paragraph 0178; 0180; 0192; 0205; 0224
(2021/08/19)
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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
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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.
- El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Elwan, Alaa
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p. 881 - 897
(2021/01/25)
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- Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation
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S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development.
- Lian, Xu,Xia, Zhonghua,Li, Xueyao,Karpov, Pavel,Jin, Hongwei,Tetko, Igor V.,Xia, Jie,Wu, Song
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- Design, synthesis, and molecular docking studies of new [1,2,4]triazolo[4,3-a]quinoxaline derivatives as potential A2B receptor antagonists
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Abstract: Many shreds of evidence have recently correlated A2B receptor antagonism with anticancer activity. Hence, the search for an efficient A2B antagonist may help in the development of a new chemotherapeutic agent. In this article, 23 new derivatives of [1,2,4]triazolo[4,3-a]quinoxaline were designed and synthesized and its structures were confirmed by different spectral data and elemental analyses. The results of cytotoxic evaluation of these compounds showed six promising active derivatives with IC50 values ranging from 1.9 to 6.4?μM on MDA-MB 231 cell line. Additionally, molecular docking for all synthesized compounds was performed to predict their binding affinity toward the homology model of A2B receptor as a proposed mode of their cytotoxic activity. Results of molecular docking were strongly correlated with those of the cytotoxic study. Finally, structure activity relationship analyses of the new compounds were explored. Graphic abstract: [Figure not available: see fulltext.]
- Ezzat, Hany G.,Bayoumi, Ashraf H.,Sherbiny, Farag F.,El-Morsy, Ahmed M.,Ghiaty, Adel,Alswah, Mohamed,Abulkhair, Hamada S.
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p. 291 - 306
(2020/03/24)
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- New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis
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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.
- 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
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- New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation
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A new series of bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives were designed and synthesized to have the main essential pharmacophoric features of VEGFR-2 inhibitors. VEGFR-2 inhibitory activities were assessed for the designed compounds. In addition, cytotoxic activity was evaluated for all derivatives against two human cancer cell lines namely, HepG-2 and MCF-7. The most cytotoxic compound 20 h was subjected to further biological investigations including cell cycle, apoptosis, caspase-3, caspase-9, BAX, and Bcl-2 analyses. Different in silico studies as docking, ADMET and toxicity were carried out. The results exhibited that compounds 20b, 20e, 20h and 20m showed promising VEGFR-2 inhibitory activities with IC50 values of 5.7, 6.7, 3.2, and 3.1 μM, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC50 values ranging from 3.3 to 14.2 μM, comparing to sorafenib (IC50 = 2.17 and 3.43 μM against HepG2 and MCF-7, respectively). Additionally, compound 20h induced cell cycle arrest of HepG2 cells at G2/M phase. Also, such compound increased the progress of apoptosis by 3.5-fold compared to the control. As well, compound 20h showed a significant increase in the level of caspase-3 (2.07-fold), caspase-9 (1.72-fold), and BAX (1.83-fold), and a significant decrease in Bcl-2 level (1.92-fold). The in silico studies revealed that the synthesized compounds have binding pattern like that of sorafenib.
- Alanazi, Mohammed M.,Mahdy, Hazem A.,Alsaif, Nawaf A.,Obaidullah, Ahmad J.,Alkahtani, Hamad M.,Al-Mehizia, Abdulrahman A.,Alsubaie, Sultan M.,Dahab, Mohammed A.,Eissa, Ibrahim H.
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- Identification of new [1,2,4]triazolo[4,3-a]quinoxalines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, anticancer evaluation, and in silico studies
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Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC50 = 8.2 and 5.4 μM, respectively), compared to sorafenib (IC50 = 3.51 and 2.17 μM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC50 = 3.4 nM) exhibited good activity compared to sorafenib (IC50 = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro‐apoptotic marker (Bax) expression by 2.33-fold and decreased anti‐apoptotic (Bcl‐2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4).
- Alsaif, Nawaf A.,Taghour, Mohammed S.,Alanazi, Mohammed M.,Obaidullah, Ahmad J.,Alanazi, Wael A.,Alasmari, Abdullah,Albassam, Hussam,Dahab, Mohammed A.,Mahdy, Hazem A.
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- Design, synthesis and molecular docking of new [1,2,4] triazolo[4,3-a]quinoxaline derivatives as anticancer agents targeting VEGFR-2 kinase
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Abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) is critically involved in cancer angiogenesis. Blocking of VEGFR-2 signaling pathway proved effective suppression of tumor growth. Accordingly, two series of new triazoloquinoxaline-based derivatives were designed and synthesized as VEGFR-2 inhibitors. All in vitro cytotoxic activities of the synthesized compounds were evaluated against two human cancer cell lines (MCF-7 and HepG2). To confirm the potential mechanism of cytotoxicity, enzymatic assays against VEGFR-2 were estimated for all the target compounds. The results of VEGFR-2 inhibitory activity and cytotoxicity were in high correlation. Compound 22a exhibited the highest cytotoxic effect with IC50 values of 6.2 and 4.9?μM against MCF-7 and HepG2, respectively, comparing to sorafenib (IC50 = 3.53 and 2.18?μM). Such derivative showed the best VEGFR-2 inhibitory activity with an IC50 value of 3.9?nM, which is very close to that of sorafenib (IC50 = 3.13?nM). Moreover, compounds 22b, 23b, and 23e exhibited strong cytotoxic activity with IC50 values ranging from 11.7 to 15.3?μM. Also, these compounds showed promising VEGFR-2 inhibition with IC50 values of 4.2, 5.7, and 4.7?nM, respectively. In silico docking, ADMET, and toxicity studies were carried out for the synthesized compounds. The results revealed that some compounds have a good binding mode against VEGFR-2 and a high level of drug-likeness. Graphic abstract: [Figure not available: see fulltext.]
- Alanazi, Mohammed M.,Alanazi, Wael A.,Alasmari, Abdullah F.,Albassam, Hussam,Alsaif, Nawaf A.,Elwan, Alaa,Mahdy, Hazem A.,Obaidullah, Ahmad J.,Taghour, Mohammed S.
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- Targeting VEGFR-2 by new quinoxaline derivatives: Design, synthesis, antiproliferative assay, apoptosis induction, and in silico studies
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Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC50 value of 3.2 nM, which is very close to that of sorafenib (IC50 = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness.
- Al-Hossaini, Abdullah M.,Al-Mehizi, Abdulrahman A.,Alanazi, Mohammed M.,Alkahtani, Hamad M.,Alsaif, Nawaf A.,Elwan, Alaa,Mahdy, Hazem A.,Obaidullah, Ahmad J.,Taghour, Mohammed S.
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- Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho-Dithiophenols
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A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho-dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho-dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3-b]quinoxaline with strong built-in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ-DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans-tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k2≈1.3 m?1 s?1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein-fishing applications and in-gel fluorescence analysis.
- Fu, Hua,Li, Hongyun,Li, Youshan,Lou, Zhenbang,Yang, Haijun,Zhao, Yufen
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supporting information
p. 3671 - 3677
(2020/02/04)
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- Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B
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A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.
- Afifi, Tarek H.,Ahmed, Hany E. A.,Alswah, Mohamed,Bayoumi, Ashraf H.,El-Gamal, Kamal M.,El-Morsy, Ahmed,Ghiaty, Adel,Mansour, Baseem Awad,Mohammed, Adel Saad,Omar, Abdelsattar M.,Sherbiny, Farag F.
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- Efficient Phosphorus-Free Chlorination of Hydroxy Aza-Arenes and Their Application in One-Pot Pharmaceutical Synthesis
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The chlorination of hydroxy aza-arenes with bis(trichloromethyl) carbonate (BTC) and SOCl2 has been effectively performed by refluxing with 5 wt % 4-dimethylaminopyridine (DMAP) as a catalyst. Various substrates are chlorinated with high yields. The obtained chlorinated aza-arenes can be used directly with simple workup for succedent one-pot synthesis on a large scale.
- Wang, Jian,Li, Yan-Hui,Pan, Song-Cheng,Li, Ming-Fang,Du, Wenting,Yin, Hong,Li, Jing-Hua
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supporting information
p. 146 - 153
(2020/03/10)
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- NHD2-15, a novel antagonist of Growth Factor Receptor-Bound Protein-2 (GRB2), inhibits leukemic proliferation
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The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a KD value of 119 ± 2 μM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.
- Lewis, Tina R.,Smith, Jesse,Griffin, Kallie,Aguiar, Stephanie,Rueb, Kristen F.,Holmberg-Douglas, Natalie,Sampson, Ellen M.,Tomasetti, Skylar,Rodriguez, Sofia,Stachura, David L.,Arpin, Carolynn C.
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- Facile synthesis and anti-proliferative activity evaluation of quinoxaline derivatives
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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.
- Li, Zhulai,Lin, Jin,Wang, Jian,Wang, Panpan,Xu, Xiuzhi,Xue, Guozhen,Zha, Daijun,Zhang, Zemin
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supporting information
(2020/01/31)
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- Synthesis and Antimicrobial Activity of Quinoxaline Based 1,2,3-Triazoles
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Abstract: Synthesis and characterization of novel quinoxaline-1,2,3-triazole hybridheterocyclic derivatives have been carried out, and their antimicrobial activityhas been tested. Antibacterial and antifungal studies of the synthesizedcompounds have demonstrated high to moderate activity against the testedpathogens for most of those. Several products have been determined to be potentantimicrobial agents at concentrations of 75 and 100 μg/mL as compared to thestandard drug Gentamicin.
- Kumar, A. Kishore,Sunitha,Ramesh,Jalapathi
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p. 2386 - 2393
(2021/02/12)
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- Design and synthesis of quinoxaline-1,3,4-oxadiazole hybrid derivatives as potent inhibitors of the anti-apoptotic Bcl-2 protein
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Quinoxaline is one of the privileged heterocyclic fragments for drug molecules. Quinoxaline anticancer drug candidates XK469 and CQS exhibit antiproliferative and proapoptotic properties against various cancers. Based on their chemical structures, we therefore synthesized a series of quinoxaline-1,3,4-oxadiazole hybrids and assessed their anticancer potential on human leukemia HL-60 cells. Although these hybrids exerted significant inhibition of HL-60 cell proliferation, they showed high cytotoxicity on human normal cells (WI-38). Utilizing information from molecular modelling of the hybrids to the anti-apoptotic Bcl-2 protein, we added substructures including phenyl, piperazine, piperidine, and morpholine rings to their frameworks. The designed quinoxaline-1,3,4-oxadiazole hybrid derivatives successfully induced apoptotic response on HL-60 cells with low toxicity on WI-38 cells. Furthermore, RT-PCR analysis demonstrated that these derivatives predominantly inhibit Bcl-2 expression. Our findings highlight the great potential for the development of synthetic quinoxaline-1,3,4-oxadiazole hybrid derivatives as proapoptotic anticancer agents.
- Ono, Yukari,Ninomiya, Masayuki,Kaneko, Daiki,Sonawane, Amol D.,Udagawa, Taro,Tanaka, Kaori,Nishina, Atsuyoshi,Koketsu, Mamoru
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- 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
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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.
- El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Elwan, Alaa
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- Structure, preparation method and application of a series of quinoxalinone derivatives
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The invention provides the structure and synthesis method of a compound shown in the formula I, and application of pharmaceutically acceptable salts of the compound or a mixture of the salts in preparation of drugs for preventing and/or treating diabetic complications. The compound acts as aldose reductase inhibitors and antioxidants and can effectively scavenge free radicals and inhibit the production of lipid peroxides by inhibiting the activity of aldose reductase, and thus the effect of preventing and/or treating the diabetic complications is achieved. The invention further provides a pharmaceutical composition containing the compound and having preventive and/or therapeutic effects on diabetic complications. The formula can be seen in the description.
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Paragraph 0051; 0054
(2019/06/27)
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- Structure, preparation method and application of quinoxalinone derivative
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The invention provides a structure and preparation of a quinoxalinone derivative (a compound as shown in formula I) and application of the pharmaceutically acceptable salt of the quinoxalinone derivative in the preparation of drugs for preventing and/or treating diabetic complication. The quinoxalinone derivative serving as a aldose reductase inhibitor and antioxidant can prevent and/or treat thediabetic complication by inhibiting the activity of aldose reductase and effectively scavenging free radicals and lipid peroxide and inhibiting active oxygen at the same time.
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Paragraph 0047; 0050
(2019/06/27)
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- Synthesis and antimicrobial activity of some new substituted quinoxalines
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A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity for the prepared compounds was investigated against four bacterial species and two fungal strains. The symmetrically disubstituted quinoxalines 2, 3, 4, and 5 displayed the most significant antibacterial activity, while compounds 6a, 6b, and the pentacyclic compound 10 showed considerable antifungal activity. Furthermore, compounds 3f, 6b showed broad antimicrobial spectrum against most of the tested strains.
- El-Atawy, Mohamed A.,Hamed, Ezzat A.,Alhadi, Mahjoba,Omar, Alaa Z.
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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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- Design, Synthesis, and Characterization of Quinoxaline Derivatives as a Potent Antimicrobial Agent
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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.
- Dewangan, Dhansay,Nakhate, Kartik,Mishra, Achal,Thakur, Alok Singh,Rajak, Harish,Dwivedi, Jaya,Sharma, Swapnil,Paliwal, Sarvesh
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p. 566 - 578
(2018/12/13)
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- Synthesis of 1-(3-phenylpropyl)-4-(pyridinylmethoxy)-[1,2,4]triazolo[4,3-a] quinoxalines
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Starting from 2,3-dichloroquinoxaline, a synthetic strategy for the preparation of 1-(3-phenylpropyl)-4-(pyridinylmethoxy)[1,2,4]triazolo[4,3-a]quinoxalines is described.
- Summer, Dominik,Matuszczak, Barbara
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- Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors
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In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Compounds 18b, 19b, 23, 25b, and 26 showed strong potencies against all tested cell lines with IC50 values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 μM, comparable with those of doxorubicin (IC50 values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 μM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC50 = 0.97 ± 0.1 and 1.10 ± 0.1 μM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 μM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC50 value of 37.06 ± 1.8 μM. Moreover, apoptosis and cell-cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G-2 cells. It has revealed cell-cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl-2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.
- Eissa, Ibrahim H.,Metwaly, Ahmed M.,Belal, Amany,Mehany, Ahmed B.M.,Ayyad, Rezk R.,El-Adl, Khaled,Mahdy, Hazem A.,Taghour, Mohammed S.,El-Gamal, Kamal M.A.,El-Sawah, Mohamad E.,Elmetwally, Souad A.,Elhendawy, Mostafa. A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.
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- Exploration of quinoxaline derivatives as antimicrobial and anticancer agents
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Novel 2 and 3-substituted quinoxaline derivatives were synthesized through various synthetic pathways, among which cyanoacetamide and cyanoacetohydrazide quinoxaline derivatives 4a-c and 11a-c, respectively, were synthesized. Furthermore, methoxy quinoxaline derivatives 3c and quinoxaline derivatives bearing substituted pyridines 6a,b, 12a,b, and 13a,b were designed to be synthesized. However, we have synthesized acrylohydrazide 5a,b and 7/acrylamide derivatives, Schiff base analogues 14a-f, pyrazole derivatives 15a-e, amide derivatives 16a-f, guanidine derivatives 16 g,h as well as, quinoxalin-2-methylallyl propionate derivative 14g. All the synthesized compounds were confirmed via spectral data and elemental analyses. Moreover, the newly synthesized compounds were evaluated for their antimicrobial activity (Gm +ve, Gm ?ve in comparison to Gentamycin a standard) and fungi (in comparison to Ketoconazole as a standard). Thus, compound 16b showed promising antimicrobial activity against B. subtilis, P. vulgaris, and S. mutants with values ranging from 20 to 27-mm zone of inhibition. While compounds 5a, 14e,f, and 16a,c,d,g,h showed potent antimicrobial activity. Moreover, the National Cancer Institute (NCI) selected 20 compounds that were submitted for anticancer screening against 60 types of cancer cell lines. The most active compounds are 5b and 12a where compound 5b containing 2,4-dichlorophenyl moiety at cyanoacetamide linkage of hydrazine quinoxaline backbone exerted significant growth inhibition activity against Leukemia MOLT-4, Renal cancer UO-31, and Breast cancer MCF-7. In addition, compound 12a having 4,6-diaminopyridinone side chain at position-3 of quinoxaline nucleus exhibited remarkable anticancer activity against renal cancer UO-31.
- Bayoumi, Ashraf H.,Ghiaty, Adel H.,Abd El-Gilil, Shimaa M.,Husseiny, Ebtehal M.,Ebrahim, Maha A.
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p. 3215 - 3235
(2019/11/16)
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- 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
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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.
- Alswah, Mohamed,Bayoumi, Ashraf H.,Elgamal, Kamal,Elmorsy, Ahmed,Ihmaid, Saleh,Ahmed, Hany E. A.
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- A One-pot Facile Synthesis of 2,3-Dihydroxyquinoxaline and 2,3-Dichloroquinoxaline Derivatives Using Silica Gel as an Efficient Catalyst
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An efficient one-pot reaction has been developed for the synthesis of 2,3-dichloroquinoxaline derivatives 3a–n. The reaction was performed in two steps via a silica gel catalyzed tandem process from o-phenylenediamine and oxalic acid, followed by addition of phosphorus oxychloride (POCl3). A variety of 2,3-dichloroquinoxalines have been obtained in good to excellent overall yields. Eight known compounds 3a–3h were characterized by IR, 1H-NMR, and mass spectroscopies. Compounds 3i–3n without spectroscopic data were characterized by IR, 1H-NMR, 13C-NMR, and mass spectroscopies.
- Zhang, Pei-Ming,Li, Yao-Wei,Zhou, Jing,Gan, Lin-Ling,Chen, Yong-Jie,Gan, Zong-Jie,Yu, Yu
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p. 1809 - 1814
(2018/07/25)
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- Design, synthesis, molecular modeling and anti-proliferative evaluation of novel quinoxaline derivatives as potential DNA intercalators and topoisomerase II inhibitors
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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 μM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 μM). 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.
- Ibrahim,Taghour,Metwaly,Belal,Mehany,Elhendawy,Radwan,Yassin,El-Deeb,Hafez,ElSohly,Eissa
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p. 117 - 134
(2018/06/08)
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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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Paragraph 0105; 0108; 0109
(2018/08/03)
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- Method for preparing 2,3-dichloro-quinoxaline derivative through one-pot procedure
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The invention belongs to the field of drug synthesis, and specifically relates to a new method for preparing 2,3-dichloro-quinoxaline derivative through one-pot procedure. According to the method, cheap o-phenylenediamine and oxalic acid are adopted as raw materials, and the cheap and easily available and environmentally friendly silica gel or methanesulfonic acid is adopted as a catalyst while steps of intermediate separation and purification are omitted; the method has the advantages of easiness in operation, low cost, mild reaction conditions and environmental friendliness and promotes industrial mass production.
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Paragraph 0019-0027
(2018/07/30)
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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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- Synthesis of Novel Substituted Phenyl-3-Hydrazinyl-Quinoxaline-2-Amine Derivatives: Evaluation of Antimicrobial Activity and Its Molecular Docking Studies
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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.
- Paliwal, Sarvesh,Sharma, Swapnil,Dwivedi, Jaya,Mishra, Achal
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p. 3689 - 3695
(2017/10/09)
-
- 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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supporting information
p. 311 - 325
(2016/09/07)
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- A kind of 2-hydrazone-thiazolo [4,5-b] quinoxaline compound and its preparation and use
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The invention relates to 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds which are characterized in that the compounds have a general formula represented as the following, wherein R is as the following. The 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds provided by the invention can be used as potential antibacterial and antitumor medicines. The invention also discloses a preparation method thereof.
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Paragraph 0017; 0018; 0025
(2017/01/09)
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- A noble transition metal complex including bisamidine moiety and method for olefin polymerization using the same
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The present invention relates to a complex compound represented by chemical formula A, and a catalyst composition for polymerizing olefin comprising the same. In the chemical formula A, M, Ar1, Ar2, R1 and R2, and the cyclic group B are the same as described in the detailed description of the invention.COPYRIGHT KIPO 2016
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Paragraph 0111-0112; 0116-0118
(2016/10/09)
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- A new small molecule inhibitor of soluble guanylate cyclase
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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.
- Mota, Filipa,Gane, Paul,Hampden-Smith, Kathryn,Allerston, Charles K.,Garthwaite, John,Selwood, David L.
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p. 5303 - 5310
(2015/11/11)
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- Synthesis of new bis(amidine)-cobalt catalysts and their application to styrene polymerization
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Two new bis(amidine) cobalt(II) complexes were rationally designed and efficiently synthesized. The first synthesized cobalt complex was based on a cyclic bis(amidine) ligand with chiral vicinal diphenyl groups. The structure was verified by single-crystal X-ray crystallography. As expected from the ligand structure, the Co-N bonds in this complex were significantly shorter than those found in the corresponding 1,2-diimine cobalt complex. This indicates that the bis(amidine) ligand has better electron-donating capability than the 1,2-diimine ligand. Upon test polymerization of styrene, the complex exhibited a moderate activity of 5.88 × 105 g PS/(mol Co h). On the basis of this encouraging result, a new 1,2-diaminobenzene-derived bis(amidine) ligand was efficiently synthesized and used to make the corresponding cobalt(II) complex. When subjected to styrene polymerization, the resulting complex showed unusually high polymerization activity [164 × 105 g PS/(mol Co h)] and high conversion (>99%). The resulting polymer was identified as atactic polystyrene by 13C NMR spectroscopy analysis. The significantly enhanced styrene polymerization activity of the 1,2-diaminobenzene-originated bis(amidine) cobalt(II) complex is attributed to the improved electron-donating capability of the ligand.
- Cho, Wonseok,Cho, Hyemin,Lee, Chun Sun,Lee, Bun Yeoul,Moon, Bongjin,Kang, Jahyo
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p. 1617 - 1622
(2014/05/06)
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- Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl}thiazoles as atypical antipsychotic agents
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A series of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were designed, synthesized, and characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The D2 and 5-HT2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized final compounds (10a-g; 11a-g; 12a-g) were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 12d, 11f, and 10a were found to be the most active compounds with 5-HT2A/D2 ratio of 1.23077, 1.14286, and 1.12857, respectively, while the standard drug risperidone exhibited 5-HT2A/D2 ratio of 1.0989. Among the twenty one new chemical entities, three compounds (12d, 11f, and 10a) were found to exhibit better atypical antipsychotic activity as they were found to have higher Meltzer index than the standard drug risperidone.
- Chandra Sekhar, Kondapalli Venkata Gowri,Rao, Vajja Sambasiva,Deuther-Conrad, Winnie,Sridhar, Divya,Nagesh, Hunsur Nagendra,Kumar, Vellas Sreedhar,Brust, Peter,Kumar, Muthyala Murali Krishna
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p. 1660 - 1673
(2013/07/26)
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- Large-scale solvent-free chlorination of hydroxy-pyrimidines,-pyridines,- pyrazines and-amides using equimolar POCl3
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Chlorination with equimolar POCl3 can be efficiently achieved not only for hydroxypyrimidines, but also for many other substrates such as 2-hydroxy-pyridines,-quinoxalines, or even-amides. The procedure is solvent-free and involves heating in a sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable for large scale (multigram) batch preparations.
- Wang, Han,Wen, Kun,Wang, Le,Xiang, Ye,Xu, Xiaocheng,Shen, Yongjia,Sun, Zhihua
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experimental part
p. 4533 - 4544
(2012/06/30)
-
- Resorcinarene-based cavitands with chiral amino acid substituents for chiral amine recognition
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Resorcinarene-based deep cavitands alanine methyl resorcinarene acid (AMA), alanine undecyl resorcinarene acid (AUA) and glycine undecyl resorcinarene acid (GUA), which contain chiral amino acids, have been synthesized. The upper rim of the resorcinarene host is elongated with four identical substituents topped with alanine and glycine groups. The structures of the new resorcinarenes were elucidated by nuclear magnetic resonance (NMR), mass spectrometry (MS) and the sustained off-resonance irradiation collision induced dissociation (SORI-CID) technique in FTICR-MS. These studies revealed that eight water molecules associate to the cavitand, two for each alanine group. The alanine substituent groups are proposed to form a kite-like structure around the resorcinarene scaffold. The binding of AMA, AUA, and GUA with chiral R- and S-methyl benzyl amines was studied by 1H NMR titration, and compared to that of a binary l-tartaric acid and the monoacid phthalyl alanine (PA). The results show that these compounds interact with amine guests; however, with four carboxylic acid groups, they bind several amine molecules strongly while the binary l-tartaric acid only binds one amine guest strongly. The simple compound PA, which contains one carboxylic group, shows weak binding to the amines. The 1H NMR titration of AUA with primary, secondary, and tertiary chiral amines showed that it can discriminate between these three types of amines and showed chiral discrimination for chiral secondary amines.
- Li, Na,Yang, Fan,Stock, Hillary A.,Dearden, David V.,Lamb, John D.,Harrison, Roger G.
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scheme or table
p. 7392 - 7401
(2012/10/08)
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- An Efficient Synthesis of Quinoxalinone Derivatives as Potent Inhibitors of Aldose Reductase
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A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC50 values ranged from 11.4 to 74.8nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.
- Yang, Yanchun,Zhang, Shuzhen,Wu, Bobin,Ma, Mingming,Chen, Xin,Qin, Xiangyu,He, Minlan,Hussain, Saghir,Jing, Chaojun,Ma, Bing,Zhu, Changjin
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experimental part
p. 823 - 835
(2012/07/17)
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- Pyrrolo[2,3-b]quinoxalines as inhibitors of firefly luciferase: Their Cu-mediated synthesis and evaluation as false positives in a reporter gene assay
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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.
- Nakhi, Ali,Rahman, Md. Shafiqur,Kishore, Ravada,Meda, Chandana Lakshmi T.,Deora, Girdhar Singh,Parsa, Kishore V.L.,Pal, Manojit
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p. 6433 - 6441
(2012/11/07)
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- Phosphonium chloride as a non-volatile chlorinating reagent: Preparation and reaction in no solvent or ionic liquid
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Reaction of triphenylphosphine with trichloroisocyanuric acid in no solvent or an ionic liquid gave the corresponding phosphonium chloride, which can be used as a cheap and safe chlorinating reagent. Conversion of hydroxyheterocycles to chloroheterocycles, carboxylic acids to carboxylic acid chlorides, and primary amides to nitriles were accomplished by using the phosphonium chloride in excellent to good yields.
- Sugimoto, Osamu,Harada, Yukihiro,Tanji, Ken-Ichi
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p. 1583 - 1590
(2013/08/15)
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- Part I: Synthesis, cancer chemopreventive activity and molecular docking study of novel quinoxaline derivatives
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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.
- Galal, Shadia A.,Abdelsamie, Ahmed S.,Tokuda, Harukuni,Suzuki, Nobutaka,Lida, Akira,Elhefnawi, Mahmoud M.,Ramadan, Raghda A.,Atta, Mona H.E.,El Diwani, Hoda I.
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experimental part
p. 327 - 340
(2011/02/25)
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