Synthesis, Spectral Characterization and Photoluminescence of 3-chloro-6-methoxy-2-(methylsulfanyl)quinoxaline in Different Solvents: An Experimental and Theoretical Investigation Using DFT.

In the present work, we synthesized 3-chloro-6-methoxy-2-(methyl sulfanyl) quinoxaline (3MSQ) using a microwave-assisted synthesis method. The physicochemical structural analysis of the synthesized compound utilizing 1H-NMR, 13C-NMR, and FT-IR spectroscopy techniques. The photophysical properties of 3MSQ was examined through absorption and fluorescence spectroscopy. Spectroscopic analyses revealed a bathochromic shift in both absorption and fluorescence spectra, attributed to the π → π* transition. Ground and excited state dipole moments was experimentally determined using the solvatochromic shift method, employing various correlations such as Lippert's, Bakhshiev's, Kawski-Chamma-Viallet's equations, and solvent polarity parameters. Our findings indicate that the excited state dipole moments exceed those of the ground state, suggesting increased polarity in the excited state. Further, the while detailed bond length, bond angles, dihedral angles, Mulliken charge distribution, ground state dipole moments and HOMO-LUMO energy gap estimated through ab initio computations using Gaussian-09W. The value of energy band gap obtained from both the methods are in good agreement. Furthermore, employing DFT computational analysis, we identified reactive centers such as electrophilic and nucleophilic sites using molecular electrostatic potential (MESP) 3D plots. Additionally, CIE chromaticity analysis was performed to understand the photoluminescent properties of 3MSQ. The insights derived from these analyses contribute to a better understanding of the molecule's electronic structure, photophysical properties, and solute-solvent interactions, thus providing valuable information regarding its behaviour and characteristics under diverse conditions. These results contribute to a comprehensive understanding of the molecular structure and properties of 3-chloro-6-methoxy-2-(methyl sulfanyl) quinoxaline (3MSQ).

Crystal structure and Hirshfeld surface analysis of ethyl 2-(7-chloro-3-methyl-2-oxo-1,2-di-hydro-quinoxalin-1-yl)acetate.

The quinoxaline moiety in the title mol-ecule, C13H13ClN2O3, is almost planar (r.m.s. deviation of the fitted atoms = 0.033 Å). In the crystal, C-H⋯O hydrogen bonds plus slipped π-stacking and C-H⋯π(ring) inter-actions generate chains of mol-ecules extending along the b-axis direction. The chains are connected by additional C-H⋯O hydrogen bonds. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯H (37.6%), H⋯O/O⋯H (22.7%) and H⋯Cl/Cl⋯H (13.1%) inter-actions.

Synthesis, crystal structure and Hirshfeld surface analysis of 2-phenyl-3-(prop-2-yn-1-yl-oxy)quin-oxaline.

In the title compound, C17H12N2O, the quinoxaline moiety shows deviations of 0.0288 (7) to -0.0370 (7) Šfrom the mean plane (r.m.s. deviation of fitted atoms = 0.0223 Å). In the crystal, corrugated layers two mol-ecules thick are formed by C-H⋯N hydrogen bonds and π-stacking inter-actions.

Quinoxaline derivatives: Recent discoveries and development strategies towards anticancer agents.

Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promises for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between January 2018 and January 2023.

Triflic Acid-Assisted Regioselective Bromination of Quinoxaline Derivatives Enables a Facile Synthesis of Polymer PTQ10.

Poly[(thiophene)-alt-(6,7-difluoro-2(2-hexyldecyloxy)quinoxaline)] (PTQ10) emerges as a promising candidate for donor materials in organic solar cells (OSCs) due to its high efficiency, simplified synthesis, and cost-effectiveness. The acceptor unit of PTQ10 is derived from the alkylation of 5,8-dibromo-6,7-difluoroquinoxaline-2-ol, emphasizing the importance of its economical synthesis for commercial viability. This study investigates triflic acid-assisted regioselective bromination of quinoxaline derivatives and proposes an alternative synthetic pathway for PTQ10. The developed route benefits from concise synthetic steps, a dependable procedure, and high overall yield. Starting with the condensation of 4,5-difluorobenzene-1,2-diamine with ethyl oxoacetate to yield 6,7-difluoroquinoxaline-2-ol, subsequent triflic acid-assisted regioselective bromination produces 5,8-dibromo-6,7-difluoroquinoxaline-2-ol in high yield. Alkylation under Mitsunobu reaction conditions yields 5,8-dibromo-6,7-difluoro-2-(2-hexyldecyloxy)quinoxaline, followed by polymerization with 2,5-distannylated thiophene under Stille reaction conditions to afford PTQ10. This research provides insights into efficient synthetic strategies for PTQ10, advancing its potential for commercial application in OSCs.

Poly[(µ-2,3-diethyl-7,8-di-methyl-quinoxaline-κ2N:N)(2,3-diethyl-7,8-di-methyl-quinoxaline-κN)-µ-nitrato-κ2O:O'-nitrato-κ2O,O'-disilver(I)].

The structure of the title compound, [C14H18N2)2Ag2](NO3)2, contains subtle differences in ligand, metal, and counter-anion coordination. One quinoxaline ligand uses one of its quinoxaline N atoms to bond to one silver cation. That silver cation is bound to a second quinoxaline which, in turn, is bound to a second silver atom; thereby using both of its quinoxaline N atoms. A nitrate group bonds with one of its O atoms to the first silver and uses the same oxygen to bond to a silver atom (related by symmetry to the second), thereby forming an extended network. The second nitrate group on the other silver bonds via two nitrate O atoms; one silver cation therefore has a coordination number of three whereas the second has a coordination number of four. One of the quinoxaline ligands has a disordered ethyl group.

Modified Donor End Caps for Binary-to-Ternary WORM Memory Conversion in N-Heteroaromatic Systems.

A series of novel A-π-D type organic small molecules have been designed, synthesized, and demonstrated for non-volatile resistive switching WORM memory application. The electron-deficient phenazine and quinoxaline units were coupled with various functionalized triphenylamine end caps to explore the structure-property correlations. The photophysical investigations displayed considerable intramolecular charge transfer, and the electrochemical analysis revealed an optimum band gap of 2.44 to 2.83 eV. These factors and the thin film morphological studies suggest the feasibility of the compounds as better resistive memory devices. All the compounds indicated potent non-volatile resistive switching memory capabilities with ON/OFF ratios ranging from 103 to 104, and the lowest threshold voltage recorded stands at -0.74 V. A longer retention time of 103 s marks the substantial stability of the devices. The phenazine-based compounds outperformed the others in terms of memory performance. Exceptionally, the compound with -CHO substituted triphenylamine exhibited ternary memory performance owing to its multiple traps. The resistive switching mechanism for the devices was validated using density functional theory calculations, which revealed that the integrated effect of charge transfer and charge trapping contributes significantly to the resistive switching phenomena.

Crystal structure and Hirshfeld surface analysis of 3-phenyl-1-{3-[(3-phenyl-quinoxalin-2-yl)-oxy]prop-yl}-1,2-di-hydro-quinoxalin-2-one.

In the title compound, C31H24N4O2, the quinoxaline units are distinctly non-planar and twisted end-to-end. In the crystal, C-H⋯O and C-H⋯N hydrogen bonds link the mol-ecules into chains extending along the a-axis direction. The chains are linked through π-stacking inter-actions between inversion-related quinoxaline moieties.

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

The cytotoxic activity, EGFR/VEGFR2 target 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 0.86 and 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, in silico molecular docking, and ADMET studies of quinoxaline-isoxazole-piperazine conjugates as EGFR-targeting agents.

In this paper, we report the synthesis of quinoxaline-isoxazole-piperazine conjugates. The anticancer activity was evaluated against three human cancer cell lines, including MCF-7 (breast), HepG-2 (liver), and HCT-116 (colorectal). The outcomes of the tested compounds 5d, 5e, and 5f have shown more potent activity when compared to the standard drug erlotinib. In a cell survivability test (MCF-10A), three potent compounds (5d, 5e, and 5f) were evaluated against the normal breast cell line, although neither of them displayed any significant cytotoxicity with IC50 values greater than 84 µM. Furthermore, the compounds 5d, 5e, and 5f were tested for tyrosine kinase EGFR inhibitory action using erlotinib as the reference drug and compound 5e was shown to be more potent in inhibiting the tyrosine kinase EGFR than sorafenib. In addition to this, molecular docking studies of compounds 5d, 5e, and 5f demonstrated that these compounds had more EGFR-binding interactions. The potent compounds 5d, 5e, and 5f were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. While the compounds 5d, 5e, and 5f followed Lipinski, Veber, Egan, and Muegge rules without any deviation.

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 quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition.

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC50 values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC50 values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor.Communicated by Ramaswamy H. Sarma.

Tritium and deuterium labelling of a kainate receptor antagonist and evaluation as a radioligand.

Kainate receptors play a crucial role in mediating synaptic transmission within the central nervous system. However, the lack of selective pharmacological tool compounds for the GluK3 subunit represents a significant challenge in studying these receptors. Recently presented compound 1 stands out as a potent antagonist of GluK3 receptors, exhibiting nanomolar affinity at GluK3 receptors and strongly inhibiting glutamate-induced currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. This study presents the synthesis of two potent GluK3-preferring iodine derivatives of compound 1, serving as precursors for radiolabelling. Furthermore, we demonstrate the optimisation of dehalogenation conditions using hydrogen and deuterium, resulting in [2H]-1, and demonstrate the efficient synthesis of the radioligand [3H]-1 with a specific activity of 1.48 TBq/mmol (40.1 Ci/mmol). Radioligand binding studies conducted with [3H]-1 as a radiotracer at GluK1, GluK2, and GluK3 receptors expressed in Sf9 and rat P2 membranes demonstrated its potential applicability for selectively studying native GluK3 receptors in the presence of GluK1 and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-blocking ligands.

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.

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 (ßo) 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.

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.

Determination of marker residues of quinoxaline-1,4-di-N-oxides and its prototype identification by liquid chromatography tandem mass spectrometry.

Quinoxaline-1,4-di-N-oxides (QdNOs), such as carbadox, olaquindox, mequindox, quinocetone, etc. are a class of antibacterial drugs. Prototype drugs residues can not be detected due to their rapid metabolism in animals. Quinoxaline-2-carboxylic acid (QCA) and 3-methyl-QCA (MQCA) are their common marker residues, so it has been always a challenge to trace the specific QdNOs drug used in food animal production. Herein, a liquid chromatography tandem mass spectrometry method was developed to determine QCA and MQCA, and meanwhile, the prototype drugs were identified by analyzing bis-desoxy QdNOs metabolites in single ion-pair monitoring mode. The method indicated that the average recoveries for QCA and MQCA were from 90 % to 105 % with relative standard deviations below 10 %, and the limits of quantification were 1.0 µg/kg. The limits of detection of five bis-desoxy QdNOs (qualitative markers) reached 0.5 µg/kg. This new analytical strategy can effectively solve the identification problem of QdNOs drugs in animal-derived food.

Challenging the anticolorectal cancer capacity of quinoxaline-based scaffold via triazole ligation unveiled new efficient dual VEGFR-2/MAO-B inhibitors.

Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC50 = 18.04 and 7.850 µM, respectively, against HCT-116cells within their EC100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC50 = 88.79 and 9.910 nM), MAO-A (IC50 = 0.763 and 629.1 nM) and MAO-B (IC50 = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics.

Design, synthesis, biological evaluation, and in silico studies of quinoxaline derivatives as potent p38α MAPK inhibitors.

A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50 = 0.042) in comparison to the standard SB203580 (IC50 = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.

Isatin-indoloquinoxaline click adducts with a potential to overcome platinum-based drug-resistance in ovarian cancer.

Herein, a series of isatin tethered indolo[2,3-b]quinoxaline hybrids was synthesized by considering the pharmacophoric features of known DNA intercalators and topoisomerase II inhibitors. The anti-proliferative properties of the synthesized compounds were evaluated against ovarian cancer cell lines (SKOV-3 and Hey A8). Four of the compounds exhibited promising anti-proliferative activities, with one of them being 10-fold more potent than cisplatin against drug-resistant Hey A8 cells. Further investigations were carried out to determine the DNA intercalating affinities of the most active compounds as potential mechanisms for their anti-proliferative activities. ADMET in silico studies were performed to assess the physicochemical, pharmacokinetics, and toxicity parameters of active compounds. This study, to the best of our knowledge, is the first report on the potential of isatin-indoloquinoxaline hybrids as structural blueprints for the development of new DNA intercalators. Additionally, it explores their potential to circumvent platinum-based resistance in ovarian cancer.