Quinoxaline Derivatives Research Articles

Emerging Trends in Quinoxaline‐based Analogs as Protein Kinase Inhibitors: Structural Developments and SAR Insights

Cancer remains a leading cause of mortality and has been recognized as a significant global health concern. Although numerous effective anticancer agents are available; most of the current drugs lack specificity, leading to common side‐effects associated with chemotherapy. Recent research, however, offers promise for developing more targeted and safer anticancer therapies through protein kinase inhibition. Quinoxaline derivatives represent a notable class of heterocyclic compounds. The extensive spectrum of biological activities demonstrated by quinoxalines has garnered substantial research interest. Quinoxaline and its derivatives have emerged as a novel class of chemotherapeutic agents with significant activity against various tumors through protein kinase inhibition. This review aims to elucidate recent advancements in the quinoxaline derivatives targeting protein kinase along with structural developments and structure‐activity relationships associated with these compounds.

Facile Synthesis of Phthalazinone/Isoindolinone Substituted Fluorescence Active Indolo[1,2‐a]quinoxaline Derivatives via ANRORC and Fluorescence Turn Off Sensing of Fe2+

AbstractSynthesis of a series of indolo[1,2‐a]quinoxaline derivatives substituted with phthalazinones/isoindolinones/carbonyl benzoylesters at C‐4 position have been accomplished under open air rt/heating conditions following ANRORC (Addition of Nucleophile, Ring Opening and Ring Closure) mechanism. Initially condensation of 2‐(1‐indolyl)‐aniline and ninhydrin generates a spirocyclic intermediate 5′H‐spiro[indene‐2,6′‐indolo[1,2‐a]quinoxaline]‐1,3‐dione, which upon reaction with various nucleophiles like hydrazine/phenylhydrazine, amines and alcohols affords C‐4 substituted indolo[1,2‐a]quinoxalines in high yield (up to ~88 %) via ANRORC. The photophysical investigation shows that the quinoxaline derivatives possess significant fluorescence property with high quantum yield (QY~11.0–17.0). The N‐phenylphthalazinone substituted indolo[1,2‐a]quinoxaline, a molecule structurally similar to 2,2′‐bipyridine system, can efficiently and selectively detect Fe2+ through fluorescence turn off sensing.

Advancing quinoxaline chemistry: Sustainable and green synthesis using L-arabinose as a catalyst

In the present study, an innovative and eco-friendly methodology for synthesizing quinoxaline derivatives has been introduced, leveraging L-arabinose as a novel catalyst. This approach not only underscores the feasibility of green chemistry in synthesizing high-purity quinoxaline derivatives but also highlights the enhanced sustainability of the process. Detailed mechanistic investigations revealed the synergistic interactions between L-arabinose and the reactants, providing a deeper understanding of the catalytic process. The synthesized compounds, due to their unique structural and electronic properties, may find promising applications in life and material sciences such as optoelectronics. Furthermore, our environmental impact assessment demonstrated significant reduction in generated waste, solvent use, and overall carbon footprint, aligning with the global agenda for sustainable development. This research marks a significant step forward in quinoxaline chemistry, promoting the adoption of green synthesis pathways while reinforcing the principles of sustainable and environment-friendly chemical practices.

Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors

Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted quinoxaline fragment containing 26e as an effective small-molecule inhibitor of ASK1, with an IC50 value of 30.17 nM. In addition, the cell survival rate of 26e at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than GS-4997, indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that 26e decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that 26e could reduce the content of T-CHO, LDL, and TG in FFA-induced LO2 cells, and had the potential to treat non-alcoholic fatty disease. These findings provide a good choice for the future development of ASK1 inhibitors.

Experimental and molecular modeling approach on the corrosion behavior of mild steel in HCl solution with quinoxaline inhibitors

Two new quinoxaline derivatives namely (E)-3-(2-chlorostyryl)quinoxalin-2(1H)-one (CSQO) & (E)-3-(2-(thiophen-2-yl)vinyl)quinoxaline-2(1H)one (TVQO) were synthesized and identified through the following methods like infrared (IR) analysis, mass spectrometry,1H NMR and 13C NMR. Weight loss, electrochemical techniques [PDP&SIE], surface analytical techniques [SEM&UV-Visible], quantum chemical calculations [DFT], and MD simulations have all been used to examine the effectiveness of CSQO and TVQO in preventing the corrosion of mild steel. According to the findings of the experiments, the inhibitors CSQO and TVQO effectively suppress the corrosion of mild steel in 1 M HCl solution, with maximum corrosion inhibition of 97.0 and 95.5% at 10−3 M for CSQO and TVQO, respectively. Based on PDP investigations, CSQO and TVQO function as mixed-type inhibitors, and their adsorption on the MS surface follows the Langmuir adsorption isotherm and the mode of adsorption is chemisorption. Both surface investigations (SEM and UV-Visible) have validated the protective layer that developed on the metal surface. DFT calculations and MD simulations were used to study the association between inhibitor molecular structure [CSQO and TVQO] and inhibitory efficacy, and they closely match the experimental findings.

A 1,2-Aryl Migration Reaction in Visible-Light-Mediated Synthesis of Quinoxaline Derivatives: Mechanistic Studies.

The synthesis of quinoxaline derivatives holds critical importance in various fields ranging from pharmaceuticals to material science. In this study, we introduce a practical light-mediated method for the efficient synthesis of quinoxaline derivatives. This approach enabled the sequential two-step, one-pot synthesis of 1,2-dihydro-2,2-diaryl-substituted quinoxalines from quinones, alkynes, and diamines. By adjusting the stoichiometric ratios and reaction conditions, the method was shifted to yield 2,3-diaryl-substituted quinoxalines exclusively, demonstrating remarkable versatility and efficiency. This switch in reaction outcomes was revealed to involve an oxidative 1,2-aryl migration through a combination of thorough experimental and computational mechanistic studies.

A simple and highly efficient catalyst-free for the synthesis of dihydro pyrido[1, 2-a]quinoxaline derivatives by four component reactions and evaluation of their antibacterial activity

In the current work, a new series of methyl-10-amino-9-cyano-6-oxo-8-aryl-6,8-dihydro-5H-pyrido[1,2-a]quinoxaline-7-carboxylate derivatives were efficiently designed and prepared using a convenient route in excellent yields by four-component reactions among benzene-1,2-diamine, dimethyl acetylenedicarboxylate, various aromatic aldehydes and malononitrile. These reactions were carried out in acetonitrile at ambient temperature under catalyst-free conditions for 7 h. The structures of the new obtained compounds were confirmed by NMR, IR, EI-MS and elemental analysis. The antibacterial activity of the synthesized products was studied using bacterial strains: Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. The results showed that all the synthesized compounds are effective against Staphylococcus aureus, Bacillus subtilis and Escherichia coli bacteria.

Fe7S8 nanosheets- catalyzed colorimetric and fluorescence dual ratio sensing for high selectivity detection of ascorbic acid

By using Fe7S8 nanosheets (NSs) as catalyst, O-phenylenediamine (OPD) as chromogenic substrate, H2O2 as oxidant, and ascorbic acid (AA) as regulator, a dual ratio colorimetric and fluorescence sensing system for determining AA was constructed. The inherent peroxidase like activity of Fe7S8 NSs enables it to catalyze the oxidation of OPD in the existence of H2O2, resulting in the formation of yellow-colored 2, 3-diaminophenazine (DAP) with a characteristic absorption peak at 450 nm and a fluorescence emission peak at 560 nm. However, the presence of AA could suppress the oxidation of OPD and induce the generation of quinoxaline derivative (QXD) 3-(dihydroxyethyl) furo [3,4-b] quinoxaline-1-one with absorption and fluorescence emission peaks located at 345 and 435 nm, respectively. Thus, employing the absorption of QXD at 345 nm and emission at 435 nm as the reporting signals, and the absorption of DAP at 450 nm and emission at 560 nm as the reference signals, a ratio colorimetric (A345/A450) and ratio fluorescence (F435/F560) dual signal detection method for AA was developed. Under the optimized conditions, the value of A345/A450 was found to be linear with AA concentration in the ranges of 1.0–40 μM and 40–100 μM, and the value of F435/F560 was strongly correlated with AA concentration in the ranges of 1.0–30 μM and 30–100 μM. When applied for the assay of AA in human serum samples, an acceptable recovery ranging from 93.1 to 106.6 % was obtained, confirming the potential of the sensing system in practical applications.

Design, Synthesis, and in vitro Evaluation of Derivatives of Quinoxaline-2- One as a Myeloperoxidase Modulator Using in silico Methods

Background: In some pathological situations, the overproduction of oxidising agents also results in oxidative damage to host cell proteins and DNA, which induces abnormal expression of inflammatory cytokines and chemokines. A recently discovered biomarker of inflammation is myeloperoxidase. Various inflammatory conditions cause the release of this enzyme into the extracellular environment. Objective: Our study aimed to design, synthesize, and in vitro evaluate derivatives of quinoxaline- 2-one as a myeloperoxidase modulator using in silico methods. Methods: A series of quinoxaline-2-one derivatives was synthesized and characterized by various analytical techniques. Further, to confirm and explore the molecular mechanism, an in silico docking study against the myeloperoxidase enzyme was performed (PDB ID: 1DNU). Results: The compounds Q1, Q2, and Q5 showed better antioxidant activity in the DPPH assay, whereas the nitric oxide scavenging assay showed the compounds Q2, Q4, and Q5 had significant activity when compared to the standard IC50 value (28.8 μg/ml). Besides, the anti-inflammatory studies showed the compounds Q1, Q3, and Q5 had better inhibition (89.79%) when compared to the standard drug aceclofenac (85.37%) at 1000 μg/ml concentration. The top three ligands for myeloperoxidase (PDB ID: 1DNU) with the highest scores in activity were found as Q2, Q1, and Q5, with scores of -13.2838, -12.5841, and -11.6906 Kcal/mol, respectively. The compounds were efficiently bound to the myeloperoxidase active site with arene-arene, arene-cation, and hydrogen bonding interactions. Conclusion: By introducing the various heterocyclic rings and deactivating and activating groups, we may produce a newer class of candidates for many infectious diseases. Thus, from the computational studies carried out, we may obtain hints for optimising the molecular selectivity of the quinoxaline-2-one derivatives to provide help in the design of new compounds for effective myeloperoxidase enzyme modulators. However, further pharmacokinetics, pharmacodynamics, preclinical, and clinical studies permit the design of the new agents without undesirable interactions.

Quinoxaline 1,4-di-N-oxide Derivatives as New Antinocardial Agents

Mycetoma is currently considered as a neglected tropical disease. The incidence of mycetoma is unknown but most of the worldwide cases are present in the “mycetoma belt” including countries like Mexico, India, Senegal, and others. The treatment of mycetoma depends on the etiological agent responsible for the case. Treatment success reaches 60 to 90%; however, common treatment has been reported to be ineffective in some cases, due in part to resistance to the prescribed antibiotics. Therefore, it is necessary to develop new therapeutic options. In the past two decades, quinoxaline derivatives have shown relevance as antibacterial agents. Therefore, in this work, esters of quinoxaline 1,4-di-N-oxide derivatives were evaluated in vitro against the reference strain CECT-3052 from N. brasiliensis, six clinical isolates, and macrophages J774A.1 to determine their cytotoxicity and security index. Additionally, nine reference drugs were evaluated as controls. The results show that nine esters of quinoxaline 1,4-di-N-oxide derivatives had a minimum inhibitory concentration (MIC) < 1 µg/mL against the reference strain and four of them (N-05, N-09, N-11, and N-13) had an MIC < 1 µg/mL against the clinical isolates. Therefore, the scaffold quinoxaline 1,4-di-N-oxide could be used to develop new and more potent antinocardial agents.

Suzuki-Miyaura coupling reaction: Blue-yellow emitting AIE active dyes for organic electronics

A series of eight novel donor‒acceptor (D─A) based 2,3-di(thiophen-2-yl)quinoxaline derivatives 2–9 were prepared by modulating donor species on quinoxaline core with Palladium catalyzed Suzuki–Miyaura ‘C–C bond’ coupling reaction. The synthesized molecules were fully characterized and studied for impact of D–A interaction on opto-electrochemical properties. Absorption spectra of 2–9 display intramolecular charge transfer (ICT) transitions in the range of 388–414 nm. Dyes shows positive solvatochromism and emit in blue‒yellow region with emission maxima 444−550 nm on excitation at their respective ICT maxima in toluene, chloroform, DCM, DMSO and neat solid film. Further, solid state emission was studied for aggregation‒induced emission (AIE) effect in THF–water system due to the nanoparticles formation, as confirmed by FEG‒SEM technique. The HOMO and LUMO energy level for compounds 2–9 were measured by cyclic voltammetry and found in the range of −5.15 to −5.94 eV and −2.81 to −3.39 eV. Theoretical studies of molecules were also carried out by using DFT and TD‒DFT calculations. The comparable HOMO and LUMO energy levels with reported ambipolar materials and efficient solid-state emission make synthesized compounds potential candidate for solid state emissive, ambipolar charge transporting materials in organic electronics.

Pragmatic Access to Hybrid Quinoxaline Scaffold Mediated by Elemental Sulfur Enabling Actualization to π-Extended and Aza-Annulated Heterocyclic Units.

A metal-free approach for synthesizing hybrid quinoxaline derivatives from sulfoxonium ylide and a 1,5-bis-nucleophilic N-heterocycle mediated by elemental sulfur is presented to illuminate the [5+1] cascade cyclization sequence. Large-scale synthesis and postsynthetic functionalizations for the annulative π-extension and intramolecular aza-annulation reactions reveal the potential utility and actualize the fabricated approach.

Dual-mode colorimetric-fluorometric immunoassay for foodborne parasitic infection

Immunoassays are the primary method used for detection of foodborne parasitic infection. The nanomaterials used in these assays often present challenges such as complex preparation requirements and low stability during long-term storage and transport. Herein, based on cost-effective K3[Fe(CN)6]-mediated in-situ generated CuFe Prussian blue analogues (CuFe-PBA) and quinoxaline derivatives with high fluorescence, a dual-mode immunoassay was proposed for foodborne parasitic infection. This platform is relied on the restoration of K3[Fe(CN)6] by ascorbic acid (AA). In addition to this process, K4[Fe(CN)6]-triggered the generation of CuFe-PBA, and the enhanced fluorogenic reaction of dehydrogenated AA and o-phenylenediamine (OPD) occur sequentially. Without complex probes preparation, the assay enabled the rapid on-site detection of ALP and foodborne parasitic infection through a colorimetric mode accessible via smartphone and offered enhanced sensitivity through a fluorescent mode. The method was used for the detection of ALP, achieving detection limits of 0.38 U/L and 0.03 U/L for colorimetric and fluorescence modes, respectively. Subsequently, the dual-mode immunoassay was applied to Trichinella spiralis infection. The sensitivity and specificity of both the colorimetric and fluorescence modes were 100 % in 950 pig serum samples. This immunosensor provides a universal analysis tool for the accurate, cost-effective and highly sensitive detection of foodborne parasitic infection

Study of transport, tissue distribution, depletion, and hepatotoxicity of Cyadox, a quinoxaline-1,4-dioxide derivative.

Cyadox (CYA) is a derivative of quinoxaline 1,4-dioxide and a safe and effective synthetic antibacterial agent. This study aimed to explore the drug transport in blood, distribution, depletion and hepatotoxicity of drugs in animals. The transport of CYA in blood was studied using fluorescence, circular dichroism (CD) and molecular docking methods. Tissue distribution and depletion of CYA in rats were evaluated following oral administration of [3H]-CYA at different doses. Hepatotoxicity of drugs evaluated by transcriptomics. During transport in the bloodstream, the drug binds to bovine serum albumin (BSA) by hydrogen bonding and has only one binding site. Hydrogen bonds were formed between O (2) of CYA and ARG208, O (3) of CYA and LEU480, VAL481. The secondary protein conformation of BSA changed after binding with an increase in α-helix and a decrease in β-strand. After a single oral administration of [3H]-CYA, it was excreted rapidly within 7days, with 34.81% from the urine and 60.25% from the feces. Higher and sustained levels of radioactivity were detected in the liver during the post-dose period, suggesting that the drug may concentrate in the liver. The transcriptomic data indicates that CYA exhibits low hepatotoxicity. However, there are indications that it may have an impact on steroid biosynthesis. This study could serve as a basis for conducting further studies on the use of CYA in food animals and improving the pharmacologic, pharmacokinetic, and toxicologic effects of CYA on food animals.

Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a–d and 6a–d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.

Microwave-Assisted Synthesis of Indoloquinoxaline Derivatives as Promising Anti-Alzheimer agents: DFT and Molecular docking Study

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. One of the major pathological features of AD is the degeneration of cholinergic neurons and associated loss of acetylcholine (ACh), a key neurotransmitter involved in memory and cognition. Reduced ACh levels correlate with the severity of cognitive symptoms in AD. Thus, inhibition of acetylcholinesterase (AChE), the enzyme responsible for breaking down ACh, is a leading treatment strategy. This study aimed to synthesize and evaluate novel AChE inhibitors based on an indolo[2,3-b]quinoxaline scaffold. A series of indolo[2,3-b]quinoxaline derivatives were designed by molecular hybridization of indole and quinoxaline privileged structures. Microwave-assisted synthesis improved the efficiency of obtaining the desired compounds. In vitro screening identified several potent AChE inhibitors, with IC50 values down to 0.02 µM. The most active compounds contained electron-withdrawing groups like nitro and benzoyl moieties. DFT calculations provided insights into geometrical, thermal, and electronic properties of the compounds. FMO analysis revealed variations in HOMO and LUMO energies that impact reactivity. Molecular docking elucidated binding modes, highlighting the pi-pi, pi-H, and H-bonding interactions with key amino acids in the catalytic gorge of AChE. Overall, the indole-quinoxaline hybrids represent promising candidates for development of novel dual binding site AChE inhibitors and multifunctional anti-Alzheimer agents.

Cancer Therapy with Quinoxaline Derivatives: Dual Inhibition of Pi3k and Mtor Signaling Pathways

Quinoxaline is a heterocyclic compound with a benzene ring fused to a pyrazine ring. It learned much about his ability to cure many diseases, including cancer. Phosphoinositide 3kinase (PI3K) and the mTOR (mammalian target of rapamycin) are the 3 essential pathways which regulate the growth, survival, and development of cells. Dysregulation of such pathways is often seen in cancer, making them attractive targets for cancer therapy. In particular, several quinoxaline derivatives show promise as two inhibitors of the mTOR/PI3K signalling pathway, which is often dysregulated in cancer along with many other diseases. One such example is PX866, which has shown activity against several cancers in previous studies. In previous studies, another quinoxaline derivative, PKI587, also showed strong inhibitory activity against mTOR and PI3K. PKI587 was researched in several clinical trials for treating many cancer types, which include non-small cell lung as well as breast cancer. Dual inhibitors of mTOR and PI3K, including quinoxaline derivatives, inhibit cell growth and cancer by blocking the signalling of these two important factors. In recent years, quinoxaline derivatives have emerged as potent dual inhibitors of PI3K and mTOR, and in this review, we explore the latest developments in this area.

Direct C–C Bond Cleavage of CH3CN as a Single‐Carbon Synthon：Synthesis of Pyrrolo[1,2‐a]quinoxalines via Electrochemical Oxidation

A direct electrochemical redox reaction involving radical cross‐coupling cyclization for the synthesis of pyrrolo[1,2‐a]quinoxaline derivatives from 1‐(2‐aminophenyl)pyrroles and CH3CN has been developed, which includes the functionalization of C(sp3)‐H bonds as well as the construction of C‐C and C‐N bonds. Notably, the control and deuterium‐labelling experiments suggest that CH3CN in this reaction acts as both a carbon source via C‐C cleavage and solvent. The reaction features metal‐ and oxidant‐free conditions, and various substituted pyrrolo[1,2‐a]quinoxaline derivatives were obtained.

Development of novel near-infrared photothermal material for efficient breast cancer therapy

Photothermal therapy (PTT) has become a candidate treatment for breast cancer due to its non-invasive, specific and controllable properties. However, there are few strategies to develop photothermal agents with high photothermal conversion efficiency, adequate tumor accumulation, and the molecular design theory is not perfect. Thus, to obtain the photothermal agent with better comprehensive performance, a novel conjugated polymer PAPQ-Th, comprising quinoxaline derivative 10,11-bis(4-(octyloxy) phenyl)acenaphtho[1,2-b]pyrazino[2,3-g]quinoxaline (PAPQ) as the acceptor and thiophene (Th) as the donor, was designed and synthesized. The PAPQ-Th exhibited the high non-radiative rate of 7.3 × 1011 s−1 and faint fluorescence emission. And PAPQ-Th nanoparticles exhibited strong NIR absorption from 650 nm to 900 nm, negligible ROS generation, and an impressively high photothermal conversion efficiency of 61 % under an 808 nm laser irradiation. Furthermore, PAPQ-Th nanoparticles can be successfully used for both in vitro and in vivo experiments, and exhibited remarkable photothermal antitumor efficacy. After intravenous administration and 808 nm laser irradiation, 4T1 tumor-bearing mice achieve complete tumor remission without recurrence. The results demonstrate that the design of new quinoxaline derivative and construction of novel donor-acceptor conjugated polymer are the effective strategy for the synthesis of efficient photothermal agent.

Experimental and theoretical investigations for novel 6-nitroquinoxaline-2,3‑dione derivatives: Synthesis, characterization, DFT calculations, ADME analysis, hirshfeld surface calculations, molecular docking studies, and antiproliferation evaluation

This work describes the synthesis of eight different 6-nitro-1,4-disubstituted-quinoxaline-2,3‑dione derivatives (4a-h). The starting material, 6-nitroquinoxaline-2,3‑dione 3 was prepared by reacting 4-nitro-o-phenylenediamine 1 with oxalic acid 2 at reflux in hydrochloric acid. Compound 3 was alkylated with various alkyl halides under solid-liquid phase transfer catalysis (PTC) to give the dialkyl quinoxalines (4a-h). The structures of all compounds obtained were elucidated based on spectroscopic measurements: 1H, 13C NMR, MS and UV spectroscopy and confirmed by single-crystal X-ray diffraction studies in the case of 4a, 4b, 4f, and 4h. The geometrical parameters and spectral data were also compared with those of a DFT geometry optimization and molecular orbital calculation at the B3LYP/6–311++G (d, p) level of theory. The closest contacts between the molecules of the four structures were investigated by analyzing their Hirshfeld surfaces and docking investigations in the protein EGFR (pdbid: 4HJO). Moreover, the experimental results are correlated to the calculated ones and showed great compatibility. Cell proliferation was used to measure the immunomodulatory activity of 4a-h compared to a control consisting only of normal cells cultured alone to determine their antiproliferative screening which concluded that the quinoxaline derivatives 4c, 4d, 4f and 4g showed immunomodulatory potential.