Quinoxaline Derivatives Research Articles

I2-Mediated Site-Selective C-H Functionalization: Access to p-Amino-Substituted Unsymmetrical Benzils and Quinoxalines from Sulfoxonium Ylides.

An I2-mediated approach for selective C-H functionalization of unprotected aniline derivatives for synthesizing benzils and quinoxaline derivatives from sulfoxonium ylides has been described. Aniline derivatives and sulfoxonium ylides ornamented with different functional groups showed good compatibility. They afforded the corresponding products with moderate to high yields via a mild and simple procedure. Finally, we validated the practicality of this method by scaling up the reaction and further conversion of the synthesized derivatives into other valuable molecules.

Synthesis of 2-aryl quinoxaline derivatives and their in silico investigation for breast cancer medication

The main objective of the present work is to synthesize and identify the potential breast cancer medication of 2-aryl quinoxaline ­derivatives via in silico investigations. Synthesis of 2-aryl quinoxaline derivatives have been achieved via the reaction of 3-aroylmethylene-2H-indol-2-ones 1 with various 1,2-diamines. Good yields were obtained at 60 °C in methanol by using graphene oxide (GO) as catalyst, however, the regio selectivity in case of unsymmetrically substituted diamines were low to moderated. This is the first report of the oxidative cleavage of C = C bond during the course of the reaction. Molecular docking study of these synthesized compounds were employed to calculate the binding affinity with human epidermal growth factor receptor 2 (HER2). 6-Bromo-3-phenylpyrido[2,3-b]pyrazine 3k showed highest binding energy of −7.70 kcal/mol depicting the potential inhibitor of HER2 receptor protein. However, this study needs to be supported by in vitro and in vivo studies.

N-allyl quinoxaline derivative exhibited potent and selective cytotoxicity through EGFR/VEGFR-mediated apoptosis: In vitro and in vivo studies.

The cytotoxic activity, EGFR/VEGFR2target inhibition, apoptotic activity, RT-PCR gene expression, in vivo employing a solid-Ehrlich carcinoma model, and in silico investigations for highlighting the binding affinity of eight quinoxaline derivatives were tested for anticancer activities. The results showed that compound 8 (N-allyl quinoxaline) had potent cytotoxicity against A594 and MCF-7 cancer cells with IC50 values of 0.86and 1.06 µM, respectively, with noncytotoxic activity against WISH and MCF-10A cells having IC50 values more than 100 µM. Furthermore, it strongly induced apoptotic cell death in A549 and MCF-7 cells by 43.13% and 34.07%, respectively, stopping the cell cycle at S and G1-phases. For the molecular target, the results showed that compound 8 had a promising EGFR inhibition activity with an IC50 value of 0.088 µM compared to Sorafenib (IC50 = 0.056 µM), and it had a promising VEGFR2 inhibition activity with an IC50 value of 0.108 µM compared to Sorafenib (IC50 = 0.049 µM). Treatment with compound 8 ameliorated biochemical and histochemical parameters near normal in the in vivo investigation, with a tumor inhibition ratio of 68.19% compared to 64.8% for 5-FU treatment. Finally, the molecular docking study demonstrated the binding affinity through binding energy and interactive binding mode inside the EGFR/VEGFR2 proteins. Potent EGFR and VEGFR2 inhibition of compound 8 suggests its potential for development as a selective anticancer drug.

Design, synthesis of novel Schiff bases as potential insecticidal agents against Spodoptera frugiperda (Lepidoptera: Noctuidae)

In the present work, novel series of Schiff base 2-7 were synthesized via treatment of p-tosyloxy benzaldehyde with some indole and quinoxaline derivatives in ethanol under reflux. All product structures were verified using elemental analysis and spectroscopic investigations, including 13C NMR, 1H NMR, and IR. Our research was conducted on the insecticidal activity, and biological effects of the recently synthesized Schiff bases on S. frugiperda. The results showed that compound 5 was the most active insecticide, nearly surpassing methomyl as a reference, with LC50 values of 46.35 mg/L for second-instar larvae and 97.37 mg/L for fourth-instar larvae. This research opened up new avenues for the search for a novel class of insecticide.
 KEY WORDS: Schiff bases, Spodoptera frugiperda, Insecticidal activity, Biological aspects, Toxicity
 Bull. Chem. Soc. Ethiop. 2024, 38(3), 765-774. 
 DOI: https://dx.doi.org/10.4314/bcse.v38i3.17

Inhibitors of Cyclophilin A: Current and Anticipated Pharmaceutical Agents for Inflammatory Diseases and Cancers.

Cyclophilin A, a widely prevalent cellular protein, exhibits peptidyl-prolyl cis-trans isomerase activity. This protein is predominantly located in the cytosol; additionally, it can be secreted by the cells in response to inflammatory stimuli. Cyclophilin A has been identified to be a key player in many of the biological events and is therefore involved in several diseases, including vascular and inflammatory diseases, immune disorders, aging, and cancers. It represents an attractive target for therapeutic intervention with small molecule inhibitors such as cyclosporin A. Recently, a number of novel inhibitors of cyclophilin A have emerged. However, it remains elusive whether and how many cyclophilin A inhibitors function in the inflammatory diseases and cancers. In this review, we discuss current available data about cyclophilin A inhibitors, including cyclosporin A and its derivatives, quinoxaline derivatives, and peptide analogues, and outline the most recent advances in clinical trials of these agents. Inhibitors of cyclophilin A are poised to enhance our comprehension of the molecular mechanisms that underpin inflammatory diseases and cancers associated with cyclophilin A. This advancement will aid in the development of innovative pharmaceutical treatments in the future.

A novel quinoxaline-based multifunctional probe: Sensitive and selective naked-eye detection of Fe3+ and fluorescent sensing of Cu2+ and its application

A new quinoxaline derivative (QM: 6-methyl-2,3-di(quinoline-2-yl)quinoxaline) was synthesized as a colorimetric and fluorescent chemosensor for detecting Fe3+ and Cu2+ ions. QM can selectively detect Fe3+ among a number of essential cations and showed an obvious colorimetric response (colorless to yellow) in the presence of Fe3+ ions and considerable fluorescence quenching response towards Cu2+ ions. The molar ratio and Job plot showed a 1:1 stoichiometric ratio for the QM-Fe3+ and QM-Cu2+ complexes. The binding constants for QM-Fe3+ and QM-Cu2+ were found to be 3.335 × 105 and 2.230 × 103 M−1, respectively, using the Benesi-Hildebrand method. The quenching rate constant (Ksv) for QM-Cu2+ was 18.8 × 103 M−1 using the Stern-Volmer plot. The limits of detection and quantification for QM-Fe3+ were calculated as 0.236 and 0.787 µM, respectively, and those for QM-Cu2+ were 0.39 and 1.31 µM, respectively. Therefore, sensor QM can be used to quantify Fe3+ and Cu2+ ions in real samples with good recovery.

Terpolymer Containing a meta-Octyloxy-phenyl-Modified Dithieno[3,2-f:2',3'-h]quinoxaline Unit Enabling Efficient Organic Solar Cells.

With the rapid development of small-molecule electron acceptors, polymer electron donors are becoming more important than ever in organic photovoltaics, and there is still room for the currently available high-performance polymer donors. To further develop polymer donors with finely tunable structures to achieve better photovoltaic performances, random ternary copolymerization is a useful technique. Herein, by incorporating a new electron-withdrawing segment 2,3-bis(3-octyloxyphenyl)dithieno[3,2-f:2',3'-h]quinoxaline derivative (C12T-TQ) to PM6, a series of terpolymers were synthesized. It is worth noting that the introduction of the C12T-TQ unit can deepen the highest occupied molecular orbital energy levels of the resultant polymers. In addition, the polymer Z6 with a 10% C12T-TQ ratio possesses the highest film absorption coefficient (9.86 × 104 cm-1) among the four polymers. When blended with Y6, it exhibited superior miscibility and mutual crystallinity enhancement between Z6 and Y6, suppressed recombination, better exciton separation and charge collection characteristics, and faster hole transfer in the D-A interface. Consequently, the device of Z6:Y6 successfully achieved enhanced photovoltaic parameters and yielded an efficiency of 17.01%, higher than the 16.18% of the PM6:Y6 device, demonstrating the effectiveness of the meta-octyloxy-phenyl-modified dithieno[3,2-f:2',3'-h]quinoxaline moiety to build promising terpolymer donors for high-performance organic solar cells.

A Focussed Analysis of β-cyclodextrins for Quinoxaline Derivatives Synthesis

Abstract: Cyclodextrins (CDs), which are a type of cyclic oligosaccharides, are widely used in supramolecular chemistry. For example, they can be used to encapsulate volatile compounds, such as drugs, within their hydrophobic cavity. This encapsulation reduces the volatility of the compounds and helps to retain their desired properties. Due to its extraordinary properties, cyclodextrins have been utilized as catalysts in numerous organic synthesis processes. An intrinsic objective of organic chemists is to optimize the efficacy of organic synthesis through the mitigation of chemical waste and energy expenditure. Utilizing water as a green solvent is, therefore, economical, environmentally sustainable, and secure. It appears that employing water in conjunction with a recyclable catalyst is the most effective method for supramolecular catalysis. As a consequence, we focused this review on the use of water as a solvent and cyclodextrin as a polymer catalyst to produce quinoxaline derivatives in an environmentally friendly and sustainable manner.

Green and Eco-friendly Synthetic Strategies for Quinoxaline Derivatives

Abstract: Advancement in green synthetic methodologies has brought a revolution in heterocyclic synthesis. Green synthesis has bypassed the classical procedures involving toxic/hazardous solvents or catalysts and improved the current environmental safety standards by many folds. Green chemistry research has continuously made significant contributions to the development of heterocyclic scaffolds both at laboratory and commercial scales. Researchers are continuously developing and exploring the principles of green chemistry for the development of novel therapeutic agents. Quinoxaline lies in the category of versatile heterocyclic motifs, which possesses a wide diversity in its derivatives as well as a broad profile of its therapeutic potential. In the past decades, many new green synthetic protocols have been developed and employed successfully for the synthesis of quinoxaline derivatives. These include the use of reusable nanocatalysts, polymers, various green solvents, tonsils, catalysts, water as a catalyst, microwave irradiation, ultrasonic waves, non-toxic metal catalysts, surfactants, etc. The present review focuses on various green synthetic procedures reported for quinoxalines along with the specializations and applications of the reactions.

Phenalenyl-Based Photocatalyst for Bioinspired Oxidative Dehydrogenation of N-Heterocycles and Benzyl Alcohols.

The environmental benefits of molecular oxygen as the oxidizing agent in oxidation reactions that synthesize fine chemicals cannot be overstated. Increased interest in developing robust photocatalysts is stimulated by the fact that the current photocatalytic transformation boom has made previously inaccessible synthetic approaches possible. Motivated by enzymatic catalysis, employing a reusable phenalenyl-based photocatalyst, we have successfully developed oxidative dehydrogenation utilizing molecular oxygen as a greener oxidant. Under photoinduced oxidative dehydrogenation conditions, different types of saturated N-heterocycles and alcohols were successfully dehydrogenated. The versatility of this bioinspired protocol is demonstrated by the fact that a wide variety of N-heteroaromatics, such as quinoline, carbazole, quinoxaline, acridine, and indole derivatives, as well as aldehydes and ketones, were successfully synthesized. Detailed mechanistic studies validate the proposed mechanism. Fluorescence lifetime and CV experiments revealed the crucial role of water on the efficiency of the reaction. The present protocol also provides chemoselectivity and scalability, leading to superior results and allowing for the functionalization of bioactive molecules at a late stage in a sustainable manner.

Substituent Impact on Quinoxaline Performance and Degradation in Redox Flow Batteries.

Aqueous redox flow batteries (RFBs) are attractive candidates for low-cost, grid-scale storage of energy from renewable sources. Quinoxaline derivatives represent a promising but underexplored class of charge-storing materials on account of poor chemical stability in prior studies (with capacity fade rates >20%/day). Here, we establish that 2,3-dimethylquinoxaline-6-carboxylic acid (DMeQUIC) is vulnerable to tautomerization in its reduced form under alkaline conditions. We obtain kinetic rate constants for tautomerization by applying Bayesian inference to ultraviolet-visible spectroscopic data from operating flow cells and show that these rate constants quantitatively account for capacity fade measured in cycled cells. We use density functional theory (DFT) modeling to identify structural and chemical predictors of tautomerization resistance and demonstrate that they qualitatively explain stability trends for several commercially available and synthesized derivatives. Among these, quinoxaline-2-carboxylic acid shows a dramatic increase in stability over DMeQUIC and does not exhibit capacity fade in mixed symmetric cell cycling. The molecular design principles identified in this work set the stage for further development of quinoxalines in practical, aqueous organic RFBs.

Synthesis, X-ray crystallography, computational investigation on quinoxaline derivatives as potent against adenosine receptor A2AAR

Quinoxaline represents one of the most important classes of heterocyclic compounds, which have exhibited a wide range of biological activities and industrial importance in many different fields. In this regard, we have synthetized two new quinoxaline derivatives. Their structures were confirmed by single-crystal X-ray analysis. The compounds show potent activity against adenosine receptors A2AAR based on structural activity relationship studies. Further molecular docking, molecular dynamics, ADMET analysis, and DFT (density functional theory) calculations were performed to understand the titled compound’s future drug candidacy. DFT computations confirmed the good stability of the synthesized compounds, as evidenced by the optimized molecular geometry, HOMO–LUMO energy gap, and intermolecular interactions. NBO analysis confirmed intermolecular interactions mediated by lone pair, bonding, and anti-bonding orbitals. All DFT findings were consistent with experimental results, indicating that the synthesized molecules are highly stable. These findings suggest that the synthesized compounds are promising candidates for further development as drugs for the treatment of A2AAR-related diseases. Communicated by Ramaswamy H. Sarma

Novel molecular hybrids of EGCG and quinoxaline: Potent multi-targeting antidiabetic agents that inhibit α-glucosidase, α-amylase, and oxidative stress

Diabetes mellitus is a multifactorial disease and its effective therapy often demands several drugs with different modes of action. Herein, we report a rational design and synthesis of multi-targeting novel molecular hybrids comprised of EGCG and quinoxaline derivatives that can effectively inhibit α-glucosidase, α-amylase as well as control oxidative stress by scavenging ROS. The hybrids showed superior inhibition of α-glucosidase along with similar α-amylase inhibition as compared to standard drug, acarbose. Most potent compound, 15c showed an IC50 of 0.50 μM (IC50 of acarbose 190 μM) against α-glucosidase. Kinetics studies with 15c revealed a competitive inhibition against α-glucosidase. Binding affinity of 15c (−9.5 kcal/mol) towards α-glucosidase was significantly higher than acarbose (−7.7 kcal/mol). 15c exhibited remarkably high antioxidant activity (IC50 = 18.84 μM), much better than vitamin C (IC50 = 33.04 μM). Of note, acarbose shows no antioxidant activity. Furthermore, α-amylase activity was effectively inhibited by 15c with an IC50 value of 16.35 μM. No cytotoxicity was observed for 15c (up to 40 μM) in MCF-7 cells. Taken together, we report a series of multi-targeting molecular hybrids capable of inhibiting carbohydrate hydrolysing enzymes as well as reducing oxidative stress, thus representing an advancement towards effective and novel therapeutic approaches for diabetes.

Synthesis of a Series of Quinoxaline Derivatives and Their Antibacterial Effectiveness Against Pathogenic Bacteria

AbstractThe pharmacological importance of quinoxaline derivatives in antibacterial research is well recognized. This study focuses on the synthesis of new 2,3‐dichloroquinoxaline derivatives containing thioether/ether groups to explore their potential as potent antibacterial agents against various pathogenic bacteria. Most of the compounds exhibited significant antibacterial properties comparable to the standard drug chlorhexidine (CHX). The derivatives of 2‐chloro‐3‐(arylthiol)quinoxaline demonstrated efficacy against Escherichia coli with minimum inhibitory concentrations (MIC) of 2.5 mg/mL and minimum bactericidal concentrations (MBC) of 2.5 to 5.0 mg/mL. These derivatives also showed similar sensitivity to Bacillus pumilus. In addition, molecular docking simulations were performed to investigate the interaction between the synthesized compounds and the DNA gyrase protein (PDB ID: 1KZN), a target for antibiotics. Among the synthesized compounds, 2,3‐bis(3‐nitrophenoxy)quinoxaline exhibited the most favourable docking score of −8.36 kcal/mol, with a binding affinity comparable to that of the reference ligand clorobiocin (−9.3 kcal/mol).

Insights into the crystal structure investigation and virtual screening approach of quinoxaline derivatives as potent against c-Jun N-terminal kinases 1

Quinoxaline derivatives are an important class of heterocyclic compounds in which N replaces one or more carbon atoms of the naphthalene ring and exhibit a wide spectrum of biological activities and therapeutic applications. As a result, we were encouraged to explore a new synthetic approach to quinoxaline derivatives. In this work, we synthesized two new derivatives namely, ethyl 4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (2) and 3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (3) respectively. Their structures were confirmed by single-crystal X-ray analysis. Hirshfeld surface (HS) analysis is performed to understand the nature and magnitude of intermolecular interactions in the crystal packing. Density functional theory using the wb97xd/def2-TZVP method was chosen to explore their reactivity, electronic stability and optical properties. Charge transfer (CT) and orbital energies were analyzed via natural population analysis (NPA), and frontier molecular orbital (FMO) theory. The calculated excellent static hyperpolarizability (βo) indicates nonlinear optical (NLO) properties for 2 and 3. Both compounds show potent activity against c-Jun N-terminal kinases 1 (JNK 1) based on structural activity relationship studies, further subjected to molecular docking, molecular dynamics and ADMET analysis to understand their potential as drug candidates. Communicated by Ramaswamy H. Sarma

Quinoxaline derivatives as potent compounds against both 3CLpro and PLpro enzymes of SARS-CoV-2 virus: an insight from experimental and theoretical approaches

Inspired by favipiravir, new quinoxaline derivatives were synthesized to study possible compounds as inhibitors of SARS-CoV-2's cysteine proteases, including 3CLpro and PLpro.

Electrochemical oxidative dehydrogenative annulation of 1-(2-aminophenyl)pyrroles with cleavage of ethers to synthesize pyrrolo[1,2-a]quinoxaline derivatives.

An array of pyrrolo[1,2-a]quinoxaline derivatives were achieved with moderate to good yields via the electrochemical redox reaction, which includes the functionalization of C(sp3)-H bonds and the construction of C-C and C-N bonds. In this atom economic reaction, THF was used as both a reactant and a solvent, and H2 was the sole by-product.

Advances in quinoxaline derivatives: synthetic routes and antiviral efficacy against respiratory pathogens

3D lung visualization showing COVID-19 infection areas alongside respiratory pathogens. The antiviral drug structure and comparison of healthy vs. infected lungs demonstrate how the drug could restore lung health.

Synthesis of quinoxalines and assessment of their inhibitory effects against human non-small-cell lung cancer cells.

Twenty-six quinoxalin derivatives were synthesized to assess their biological activities against human non-small-cell lung cancer cells (A549 cells). Compound 4b (IC50 = 11.98 ± 2.59 μM) and compound 4m (IC50 = 9.32 ± 1.56 μM) possess anticancer activity comparable to 5-fluorouracil (clinical anticancer drug) (IC50 = 4.89 ± 0.20 μM). Western blot tests further confirmed that compound 4m effectively induced apoptosis of A549 cells through mitochondrial- and caspase-3-dependent pathways. The introduction of bromo groups instead of nitro groups into the quinoxaline skeleton has been shown to provide better inhibition against lung cancer cells in this article. This modification in the molecular structure could enhance the biological activity and effectiveness of quinoxaline derivatives in the design and synthesis of anticancer drugs, making bromo-substituted quinoxalines a promising avenue for further research and development in anticancer therapeutics.

Synthesis and computational evaluation of the antioxidant activity of pyrrolo[2,3-b]quinoxaline derivatives.

Pyrrolo[2,3-b]quinoxaline derivatives are known to possess antioxidant, anticancer, and antibacterial properties. Here we report the successful synthesis of five derivatives of 3-hydroxy-3-pyrroline-2-one through substitution. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was employed to evaluate the antioxidant activity of the compounds. Out of these, ethyl 1,2-diphenyl-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylate (3a) demonstrated the greatest potential as a radical scavenger. Thermodynamic and kinetic calculations of the radical scavenging activity indicated that 3a exhibited HO˙ radical scavenging activity with the overall rate constant of 8.56 × 108 M-1 s-1 in pentyl ethanoate; however, it was incapable of scavenging hydroperoxyl radicals in nonpolar media. In non-polar environments, the hydroxyl radical scavenging capability of 3a is fairly similar to that of reference antioxidants such as Trolox, melatonin, indole-3-carbinol, and gallic acid. Hence, in the physiological lipid environment, 3a holds promise as a scavenger of HO˙ radicals.