2213-63-0Relevant articles and documents
Determinants of activity at human toll-like receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of diverse heterocyclic scaffolds
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.
, p. 7955 - 7970 (2014)
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.
Functionalization of gold nanoparticles with two aminoalcohol-based quinoxaline derivatives for targeting phosphoinositide 3-kinases (PI3Kα)
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.
, p. 1803 - 1811 (2019)
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.
Synthesis, structural, catecholase, tyrosinase and DFT studies of pyrazoloquinoxaline derivatives
Bouanane, Zohra,Bounekhel, Mahmoud,Elkolli, Meriem,Abrigach, Farid,Khoutoul, Mohamed,Bouyala, Rabab,Touzani, Rachid,Hellal, Abdelkader
, p. 238 - 246 (2017)
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.
One-pot synthesis of novel substituted quinoxaline piperazine derivatives and their antimicrobial activities
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
, (2022/01/06)
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.
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.
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 (2021/01/25)
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.
Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation
Lian, Xu,Xia, Zhonghua,Li, Xueyao,Karpov, Pavel,Jin, Hongwei,Tetko, Igor V.,Xia, Jie,Wu, Song
, (2021/06/15)
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.
Design, synthesis, and molecular docking studies of new [1,2,4]triazolo[4,3-a]quinoxaline derivatives as potential A2B receptor antagonists
Ezzat, Hany G.,Bayoumi, Ashraf H.,Sherbiny, Farag F.,El-Morsy, Ahmed M.,Ghiaty, Adel,Alswah, Mohamed,Abulkhair, Hamada S.
, p. 291 - 306 (2020/03/24)
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.]
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
, (2021/03/16)
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.
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
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.
, (2021/06/15)
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.
