Quinoxaline Derivatives Research Articles

Pyridine-2-yl Quinoxaline (2-CPQ) Derivative As a Novel Pink Fluorophore: Synthesis, and Chemiluminescence Characteristics.

Quinoxaline derivatives are well-known N-heterocycles with pharmacological and fluorescence activities. Almost all quinoxaline derivatives with extensive π-conjugation have been introduced as fluorophores which emit blue and green light. For the first time, we designed and synthesized 6-chloro-2,3 di(Pyridine-2yl) quinoxaline (2-CPQ) as a pink fluorophore in acetonitrile medium by simple route at room temperature whitin 30min. The synthesized quinoxaline was identified using 1H, 13C NMR, MS, and FT-IR spectroscopy. Our results showed that the iodine-catalyzed method for both oxidation and cyclization during the synthesis of quinoxaline from pyridine 2-carbaldehyde was straightforward, efficient, and clean. All of the mentioned characterization devices confirmed the synthesis of 2-CPQ.Moreover, we studied the photophysical properties of the synthesized fluorophore in which The UV-Vis absorption spectrum of 2-CPQ in DMF were three peaks at 451, 518 and 556nm. Based on photophysical properties investigation, 2-CPQ shows good fluorescence with maximum peaks 607 and 653nm in DMF as solvent (фF = 0.21). Hence, the fluorophore was applied in the peroxyoxalate chemiluminescence system. The reaction of imidazole, H2O2, and bis (2,4,6-trichlorophenyl) oxalate (TCPO) can transfer energy to a 6-chloro-2,3 di(pyridine-2yl) quinoxaline. In this process, dioxetane was synthesized, which chemically initiated the electron exchange luminescence (CIEEL) mechanism and led to pink light emission. We anticipate our synthesized fluorophores 2-CPQ will have great potential applications in imaging and medical markers.

Molecular modelling studies and synthesis of novel quinoxaline derivatives with potential inhibitory effect on GSK-3β


 
 
 
 Purpose: To synthesize quinoxaline derivatives and investigate their inhibitory effects on glycogen synthase kinase (GSK)-3β in vitro.
 Methods: Quinoxaline derivatives were synthesized via reaction between synthon 1 and DL- 2-amino succinic acid, and subsequent lactamization reaction. The new compounds were tested against GSK-3β in vitro to select the most potent compound which was then used for molecular modelling.
 Results: Novel quinoxaline derivatives with quinolone nucleus were successfully synthesized via simple chemical reactions. The compounds markedly inhibited GSK-3β, with compound 45 [3-(carboxymethyl)- 5-fluoro-10-(4-fluorophenyl)-2,7-dioxo-1,2,3,4,7,10-hexahydropyrido [2,3-f] quinoxaline-8-carboxylic acid] achieving the best effect (IC50 = 0.18 μM). The half maximal inhibitory concentrations (IC50) of the compounds were in micromolar range. Molecular modelling revealed several interactions between compound 45 and the binding site of GSK-3β.
 Conclusion: These results indicate that 3-(carboxymethyl)-5-fluoro-10-(4-fluorophenyl)-2,7-dioxo- 1,2,3,4,7,10-hexahydropyrido [2,3-f] quinoxaline-8-carboxylic acid is a potent inhibitor of GSK-3β and is thus a promising scaffold for the development of novel drugs that can effectively inhibit GSK-3β signaling pathway.
 
 
 

Green Synthesis of Indeno[1,2-b]quinoxalines Using β-Cyclodextrin as Catalyst.

An efficient, mild, and green method was developed for the synthesis of indeno[1,2-b]quinoxaline derivatives via o-phenylenediamine (OPD) and 2-indanone derivatives utilizing β-cyclodextrin (β-CD) as the supramolecular catalyst. The reaction can be carried out in water and in a solid state at room temperature. β-CD can also catalyze the reaction of indan-1,2-dione with OPD with a high degree of efficiency. Compared to the reported methods, this procedure is milder, simpler, and less toxic, making it an eco-friendly alternative. In addition, the β-CD can be recovered and reused without the loss of activity.

Molecular structural investigations of quinoxaline derivatives through 3D-QSAR, molecular docking, ADME prediction and pharmacophore modeling studies for the search of novel antimalarial agent

In the present article, a dataset of 63 quinoxaline derivatives were taken for antimalarial activity and pharmacophore were developed. Atom based method was used to develop a three dimensional quantitative structure activity relationship (3D-QSAR) model. On comparison of all statistical parameters, model AHRRR23 was found to be the most effective and predictive QSAR model as it satisfied all statistical parameters of a good model. The model AHRRR23 showed an adequate R2 value for the training set 0.9446, good predictive power with Q2 of 0.6409, good F- value, low SD 0.1218 value and outstanding Pearson-R values and low RMSE 0.2779 values of the model. The docking studies also gives very good results with good RMSD values. 3D QSAR, docking and ADME studies exhibits that the developed model could be employed as a potential lead for further study as antimalarial drug.

Novel quinoxaline derivatives as dual EGFR and COX-2 inhibitors: synthesis, molecular docking and biological evaluation as potential anticancer and anti-inflammatory agents.

Novel quinoxaline derivatives (2a–d, 3, 4a, 4b and 5–15) have been synthesized via the reaction of 4-methyl-3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (1) with different aldehydes, ketones, diketones, ketoesters, as well as hydrazine, phenyl isothiocyanate, carbon disulphide. The synthesized products have been screened for their in vitro anticancer and COX inhibitory activities. Most of the synthesized compounds exhibited good anticancer and COX-2 inhibitory activities. MTT assay revealed that compounds 11 and 13 were the most potent and exhibited very strong anticancer activity against the three cancer cell lines with IC50 values ranging from 0.81 μM to 2.91 μM. Compounds 4a and 5 come next and displayed strong anticancer activity against the three cancer cell lines with IC50 values ranging from 3.21 μM to 4.54 μM. Mechanistically, compounds 4a and 13 were the most active and potently inhibited EGFR with IC50 = 0.3 and 0.4 μM, respectively. Compounds 11 and 5 come next with IC50 = 0.6 and 0.9 μM, respectively. Moreover, compounds 11 and 13 were the most potent as COX-2 inhibitors and displayed higher potency against COX-2 (IC50 = 0.62 and 0.46 μM, respectively) more than COX-1 (IC50 = 37.96 and 30.41 μM, respectively) with selectivity indexes (SI) of 61.23 and 66.11, respectively. Compounds 4a and 5 comes next with IC50 = 1.17 and 0.83 μM and SI of 24.61 and 48.58, respectively. Molecular docking studies into the catalytic binding pocket of both protein receptors, EGFR and COX-2, showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and Veber's standard were calculated and revealed that compounds 4a, 5, 11 and 13 had a reasonable drug-likeness with acceptable physicochemical properties. Therefore, based on the obtained biological results accompanied with the docking study and physicochemical parameters, it could be concluded that compounds 4a, 5, 11 and 13 could be used as promising orally absorbed dual anti-inflammatory agents via inhibition of COX-2 enzyme and anticancer candidates via inhibition of EGFR enzyme and could be used as a future template for further investigations.

PM3 Method based QSAR Study of the Derivatives of Thiadiazole and Quinoxaline for Antiepileptic Activity using Topological Descriptors

QSAR study of the derivatives of thiadiazole and quinoxaline has been performed for the antiepileptic activity using the topological descriptors viz., molar refractivity, shape index (basic kappa, order 1), shape index (basic kappa, order 2), shape index (basic kappa, order 3), valence connectivity index (order 0, standard), valence connectivity index (order 1, standard) and valence connectivity index (order 2, standard). In the best QSAR model, the descriptors are molar refractivity, shape index (basic kappa, order 1), shape index (basic kappa, order 3) and valence connectivity index (order 0, standard). In this QSAR model, the regression coefficient is 0.872435 and cross-validation coefficient is 0.832189, which indicate that this QSAR model can be used to predict the antiepileptic activity of any compound belonging to this series. QSAR model developed using single descriptor shape index (basic kappa, order 1) or shape index (basic kappa, order 3) or valence connectivity index (order 2, standard) also has good predictive power.

A direct entry to polycyclic quinoxaline derivatives via I2-DMSO mediated oxidative decarboxylation of α-amino acids and the subsequent Pictet-Spengler cyclization reaction.

A facile and highly efficient iodine-promoted strategy has been delineated for the synthesis of indolo and pyrrolo[1,2-a]quinoxaline derivatives via an oxidative Pictet-Spengler type amino cyclo-annulation reaction using ∝-amino acids as aldehyde surrogates. The concomitant benzylic oxidation and the compatibility of different starting materials under standard conditions made the current method versatile. The salient features of the protocol such as readily available starting materials, inexpensive promoters, environmental benignity, broad substrate scope, scalability, and good to excellent yield make the method more attractive to practitioners of organic synthesis.

Design, synthesis of new novel quinoxalin-2(1H)-one derivatives incorporating hydrazone, hydrazine, and pyrazole moieties as antimicrobial potential with in-silico ADME and molecular docking simulation

A series of 6-(morpholinosulfonyl)quinoxalin-2(1 H )-one based hydrazone, hydrazine, and pyrazole moieties were designed, synthesized, and evaluated for their in vitro antimicrobial activity. All the synthesized quinoxaline derivatives were characterized by IR, NMR ( 1 H / 13 C), and EI MS. The results displayed good to moderate antimicrobial potential against six bacterial, and two fungal standard strains. Among the tested derivatives, six quinoxalin-2(1 H )-one derivatives 4a , 7 , 8a , 11b , 13 , and 16 exhibited a significant antibacterial activity with MIC values (0.97–62.5 µg/mL), and MBC values (1.94–88.8 µg/mL) compared with Tetracycline (MICs = 15.62–62.5 µg/mL, and MBCs = 18.74–93.75 µg/mL), and Amphotericin B (MICs = 12.49–88.8 µg/mL, and MFC = 34.62–65.62 µg/mL). In addition, according to CLSI standards, the most active quinoxalin-2(1 H )-one derivatives demonstrated bactericidal and fungicidal behavior. Moreover, the most active quinoxaline derivatives showed a considerable antibacterial activity with bactericidal potential against multi-drug resistance bacteria (MDRB) strains with MIC values ranged between (1.95–15.62 µg/mL), and MBC values (3.31–31.25 µg/mL) near to standard Norfloxacin (MIC = 0.78–3.13 µg/mL, and MBC = 1.4–5.32 µg/mL. Further, in vitro S. aureus DNA gyrase inhibition activity were evaluated for the promising derivatives and displayed potency with IC 50 values (10.93 ± 1.81–26.18 ± 1.22 µM) compared with Ciprofloxacin (26.31 ± 1.64 µM). Interestingly, these derivatives revealed as good immunomodulatory agents by a percentage ranging between 82.8 ± 0.37 and 142.4 ± 0.98 %. Finally, some in silico ADME, toxicity prediction, and molecular docking simulation were performed and showed a promising safety profile with good binding mode.

Design and synthesis of antivirals benzimidazoles and quinoxalines

Background Chronic hepatitis C can cause serious, even deadly, health problems like cirrhosis and liver cancer. There is no vaccine for hepatitis C. The hepatitis C virus (HCV) NS5B gene encodes RNA-dependent RNA polymerase, which is a key player in viral replication and is a promising target for the development of antiviral drugs. Drugs having benzimidazole and quinoxaline scaffolds were described to selectively block the activity of NS5B polymerase. New antiviral drugs have to be developed to overcome drug resistance.Objective The main goal of this work was to develop new effective anti-bovine viral diarrhea virus (BVDV) and anti-HCV agents by designing and synthesizing benzimidazole and quinoxaline derivatives.Materials and methods Synthesis of target compounds based on benzimidazole and quinoxaline scaffolds according to reported methods was done. Antiviral activity against BVDV was studied. BVDV and Madin-Darby bovine kidney cells were obtained from the American Type Culture Collection. Antiviral activity against HCV infectious system was evaluated. Huh7.5.1 cells were cultured and treated with different concentrations of studied compounds. GOLD molecular docking study was evaluated. The crystal structures of the HCV polymerases in complex with its co-crystalized native ligand were retrieved from the Protein Data Bank. Acute toxicity studies were carried out on animals. Results and conclusion A rational design based on the previous work was performed to indicate new promising benzimidazole and quinoxaline derivatives to be synthesized and tested as anti-HCV compounds. New benzimidazole and quinoxaline derivatives were synthesized and tested for anti-BVDV activity. All of the compounds showed strong activity against BVDV, except 17, which exhibited moderate antiviral activity. Compounds 12 and 13 were the most promising. The anti-HCV activity of 12 and 13 was investigated after infection of Huh 7.5.1 cells with HCV (JFH1). The IC50 values of 12 and 13 were found to be 19.1 and 49.4 μM, respectively; their CC50 values were 752.25 and 1480 μM, respectively; and their SI were calculated to be 39.3 for 12 and 30.03 for 13. The assigned compounds were docked into the hepatitis-C virus polymerase enzyme (pdb: 3FRZ) using GOLD 5.2.2 docking program. They revealed GoldScore fitness activities of 69.78–80.71, which is comparable to the native ‘PF-00868554’ ligand as a potent HCV polymerase inhibitor. They are bound by up to three hydrogen bonds, mainly with aminoacids R422 and S476, as well as they were embedded into the two small hydrophobic pockets formed by amino acid residues including L419, M423, L482,and L497. The acute toxicity of compound 12 on rats was tested. No signs of toxicity, no deaths, and no significant changes were observed in the biochemical parameters of liver and kidneys.

Quinoxaline derivatives as a promising scaffold for breast cancer treatment

Different mechanisms of action for the quinoxaline moiety to fight breast cancer.

Evaluation of antibacterial efficacy and molecular docking studies of quinoxaline and benzthiazole-containing benzamide derivatives

A series of benzamide derivatives (4a–4f) containing quinaxoline and benzthiazole were synthesized. All synthesized compounds were characterized using a variety of spectrum approaches, including IR, 1H NMR, Mass spectrometry. The antibacterial activity of derivatives was tested in vitro against gram-positive and gram-negative bacterial strains using an agar well diffusion assay. The FLARE V5 software was used to conduct docking studies, and all the synthesized analogs had good docking score ranging from −10.95 to −8.94 kcal/mol against target DNA Gyrase (PDB ID 4KTN). Among all analog (4f) had the highest docking score of all the compounds and was determined to be in agreement with in vitro research.

Theoretical and experimental insights into the properties of donor–σ–acceptor type derivatives of quinoxaline and methanone containing different donor moieties

A strategy of fused electron accepting moieties was employed to synthesise a series of donor-substituted quinoxaline–methanone derivatives as red TADF emitters.

Synthesis of novel antibacterial and antifungal quinoxaline derivatives.

A series of quinoxaline derivatives were designed, synthesized and evaluated as antimicrobial agents against plant pathogenic bacteria and fungi. Some of these compounds exhibited significant antibacterial and antifungal activities in vitro. Compound 5k displayed good antibacterial activity against Acidovorax citrulli (Ac). Compounds 5j and 5t exhibited the most potent anti-RS (Rhizoctonia solani) activity, with the corresponding EC50 values of 8.54 and 12.01 μg mL−1, respectively, which are superior to that of the commercial azoxystrobin (26.17 μg mL−1). Further, the scanning electron microscopy results proved that compound 5j had certain effects on the cell morphology of RS. Moreover, an in vivo bioassay also demonstrated that the anti-RS activity of compound 5j could effectively control rice sheath blight. These results indicate that quinoxaline derivatives could be promising agricultural bactericides and fungicides.

Quantum chemical and photophysical properties of 9-Chloro 2, 6-Dimethyl 10(Methylsulfanyl)Quinoxaline

In this article we worked on comparative study of photophysical property and detailed theoretical study of quinoxaline derivative 9-chloro-2,6-dimethyl 10(methylsulfanyl)quinoxaline (9Cl2,6Dm10MsQ). The molecule have been synthesized by cyclization approach, the molecular geometry was studied through the use of density functional theory (DFT) with the assist of Gaussian 09 program. The UV − visible absorption spectra and fluorescence spectra of 9Cl2,6Dm10MsQ were investigated in vacuum and different solvents having distinctive polarities. The synthesised compound absorb in the range of 372.3 nm to 376.7 nm experimentally and 362 nm to 370 nm theoretically, hence the experimental observations show the deviation with theoretical time-dependent density functional theory (TD-DFT) based on quantum analysis, The energy band gap was determined by frontier molecular orbital (FMO) evaluation and dipole moment of molecule in vacuum and liquid phase were studied using DFT with Becke’s 3 Lee–Yang– Parr (B3LYP) functional and 6-311 + G (d, p) basis set. The electron density distribution and chemical reactive sites of 9Cl2,6Dm10MsQ have been simulated from molecular electrostatic potential (MEP) which shows that, the nitrogen atomic sites have minimum potential distribution region then all other atoms of the titled molecule. These outcomes offer a deep knowledge of shape of the molecule, spectroscopic study and molecular orbital analysis in vacuum and liquid phase characteristics of the molecule leads to better understanding of molecule in different medium, which helps to study biological properties of the molecule. This compound could help to design more efficient functional optoelectronic devices.

Investigation of Toxic ?- Dicarbonyl Compounds Formed in the Headspace of Various Heated Cooking Oils

Glyoxal, methylglyoxal, and diacetyl formed in the headspace of heated oil samples were analyzed as corresponding quinoxaline derivatives. Formation of these compounds increased in the gutter oil as the number of heating repetitions increased. In particular, methylglyoxal increased from 198.43 ± 92.9 µg to 432.16 ± 161.86 µg. The total phenolic compounds in four extra virgin olive oils ranged from 231.01 ± 16.75 µg/g to 492.78 ± 39.34 µg/g (Olio Nuovo olive oil). The carbonyl compounds formed from the Olio Nuovo oil ranged from 52.76 ± 11.26 µg (glyoxal) at 150°C for 0.5 h to 801.22 ± 147.88 µg (diacetyl) at 300°C for 1 h Addition of cysteine reduced the formation of all three α-dicarbonyl compounds significantly, suggesting that cysteine forms adducts with carbonyl compounds. Standard antioxidant BHT reduced formation of all three compounds at lower heating temperatures, whereas standard antioxidant vitamin E increased them considerably at higher temperatures, suggesting that vitamin E degrades into carbonyl compounds.

Crystal structure elucidation, Hirshfeld surface analysis, and DFT studies of a N-benzyl-3-phenylquinoxalin-2-amine

Quinoxaline derivatives are important scaffolds in the heterocyclic compounds. They have shown extensive medicinal properties in biological and pharmaceutical fields. The title compound crystallizes in the monoclinic crystal system with the space group P21/c. The structure exhibits N-H...C intermolecular interaction. The crystal structure is further reinforced by π-π interactions. The Hirshfeld surface analysis indicates that the dominant contribution to the surface area is from H-H (53.4%) contacts. Density functional theory (DFT) calculations were performed with B3LYP/6–31 + G(d, p) method. The optimized structure and experimental crystal structures are very similar. The HOMO-LUMO energy gap of the compound is 4.02 eV. Molecular electrostatic potential surface shows the chemical reactive regions around the nitrogen and hydrogen atoms. Molecular docking studies was performed to analyze the anticancer the activity of the molecule.

Synthesis of novel hybrid quinoxaline containing triazole and acetamide moieties by azide-alkyne click chemistry: Experimental and theoretical characterization

Heterocyclic compounds bearing triazole and quinoxaline possess significant pharmacological activities. Herein, a new quinoxaline derivative containing 1,2,3-triazole moiety was synthesis using a copper-catalyzed azide−alkyne cycloaddition (CuAAC) “click” procedure. The solid state crystal structures of 2-azido-N-(4-methoxyphenyl)acetamide (AMA) and N-(4-methoxyphenyl)-2-(4-((3-methyl-2-oxoquinoxalin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamide (QTA) were determined by X-ray structure analysis. Density Functional Theory (DFT) computations were performed using DFT/B3LYP with 6–311++G(d,p) basis set in the gas phase to get the optimized geometry of both molecules and detailed insights into the molecular and chemical properties that are inaccessible by experimental ways like global reactivity descriptors and Fukui functions. DFT calculations at the same level of theory, with the POP=NBO keyword, were used to evaluate charge delocalization and hyperconjugative interactions through Natural Bond orbital (NBO) analysis. In the title molecule, C21H20N6O3, the quinoxaline moiety is essentially planar while the whole molecule adopts an approximate "U" shape. In the crystal, the molecules form inversion dimers through slightly slipped π-stacking interactions between quinoxaline units. These form chains extending along the a-axis direction by a combination of additional π-stacking interactions as well as N—H···N and C—O···O hydrogen bonds and C—H···π(ring) interactions. The chains are connected by C—H···O and C—H···N hydrogen bonds. In the azide compound an intramolecular C—H···O hydrogen bond helps to establish the rotational orientation of the acetamide group. In the crystal, a stepped arrangements of ribbons approximately parallel to (10¯ 1) is formed by a combination of N—H···O, C—H···O and C—H···N hydrogen bonds. Furthermore, to evaluate the chemical reactivity and charge distribution on molecules, molecular electrostatic potential (MEP) maps and atomic charges, computed by NBO theory were determined. Additionally, local reactive properties of AMA and QTA were determined using Fukui functions and dual descriptor calculations.

Synthesis of Quinoxaline Derivatives as Intermediates to Obtain Erdafitinib

Synthesis of Quinoxaline Derivatives as Intermediates to Obtain Erdafitinib

11H-Indeno[1,2-b]quinoxalin-11-one 2-(4-ethylbenzylidene)hydrazone

11H-Indeno[1,2-b]quinoxaline derivatives present an important type of nitrogen-containing heterocyclic compound that are useful intermediate products in organic synthesis and have potential pharmaceutical applications. A new 11H-indeno[1,2-b]quinoxalin-11-one-2-(4-ethylbenzylidene)hydrazone (compound 3) was synthesized. Compound 3 is the first example of an azine derivative based on the 11H-indeno[1,2-b]quinoxaline system. The Z,E-isomerism of compound 3 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, compound 3 is potentially highly bioavailable and has potential to be used for the treatment of neuroinflammation and ischemia–reperfusion injury.

Nanostructured Mesoporous Zinc-Incorporated Copper Oxide (NMZI-CuO): An Efficient and Reusable Nanocatalyst for the Oxidant-Free Synthesis of Quinoxalines through a Tandem Oxidation Process

A nanostructured mesoporous zinc-incorporated copper oxide with different Cu/Zn molar ratios was prepared through a facile hydrothermal template-free route. Textural properties of prepared materials were studied with various techniques such as TEM, BET, XRD, FTIR, and XPS. The prepared mesoporous zinc-incorporated copper oxide was then successfully applied as a heterogeneous catalyst for the synthesis of quinoxaline derivatives from 1,2-diamines and α -hydroxy ketones through a tandem oxidation process (TOP) without any oxidant. Using this method all desired products were obtained with good to excellent yields in relatively short times under solvent-free conditions. The applied catalyst was simply isolated and reused several times without any detectable loss of catalytic activity.