Design, synthesis, and biological evaluation of novel quinoxaline aryl ethers as anticancer agents.

We designed and synthesized thirty novel quinoxaline aryl ethers as anticancer agents, and the structures of final compounds were confirmed with various analytical techniques like Mass, 1 H NMR, 13 C NMR, FTIR, and elemental analyses. The compounds were tested against three cancer cell lines: colon cancer (HCT-116), breast cancer (MDA-MB-231), prostate cancer (DU-145), and one normal cell line: human embryonic kidney cell line (HEK-293). The obtained results indicate that two compounds, FQ and MQ, with IC50 values < 16 µM, were the most active compounds. Molecular docking studies revealed the binding of FQ and MQ molecules in the active site of the c-Met kinase (PDB ID: 3F66, 1.40 Å). Furthermore, QikProp ADME prediction and the MDS analysis preserved those critical docking data of both compounds, FQ and MQ. Western blotting was used to confirm the impact of the compounds FQ and MQ on the inhibition of the c-Met kinase receptor. The apoptosis assays were performed to investigate the mechanism of cell death for the most active compounds, FQ and MQ. The Annexin V/7-AAD assay indicated apoptosis in MDA-MB-231 cells treated with FQ and MQ, with FQ (21.4%) showing a higher efficacy in killing MDA-MB-231 cells than MQ (14.25%). The Caspase 3/7 7-AAD assay further supported these findings, revealing higher percentages of apoptotic cells for FQ-treated MDA-MB-231 cells (41.8%). The results obtained from the apoptosis assay conclude that FQ exhibits better anticancer activity against MDA-MB-231 cells than MQ.

Rapid immunoassays for the detection of quinoxalines and their metabolites residues in animal-derived foods: A review.

Quinoxalines are a class of veterinary drugs with antibacterial and growth-promoting functions. They are often widely used to treat and prevent animal diseases and are illegally used as animal growth promoters to increase economic benefits. Quinoxalines could be easily metabolized in animals to various residue markers and remain in animal-derived foods, which would pose a serious threat to human health. Consequently, it is necessary to detect the residues of quinoxalines and their metabolites. This article reviewed and evaluated immunoassays for quinoxalines and their metabolites in animal-derived foods, mainly including enzyme-linked immunosorbent assays, fluorescence immunosorbent assays, immunochromatography, and surface plasmon resonance biosensors. In addition, we deeply explored the design of haptens for quinoxalines and their metabolites and analyzed the effect of haptens on antibody performance. This paper aims to provide guidance and references for their accurate and sensitive detection, thereby ensuring food safety and human public health.

Green Light Promoted Iridium(III)/Copper(I)-Catalyzed Addition of Alkynes to Aziridinoquinoxalines Through the Intermediacy of Azomethine Ylides.

This manuscript describes the development of alkyne addition to the aziridine moiety of aziridinoquinoxalines using dual Ir(III)/Cu(I) catalytic system under green light-emitting diode (LED) photolysis (λmax =525 nm). This mild method features high levels of chemo- and regioselectivity and was used to generate 30 highly functionalized substituted dihydroquinoxalines in 36-98 % yield. This transformation was also carried asymmetrically using phthalazinamine-based chiral ligand to provide 9 chiral addition products in 96 : 4 to 86 : 14 e.r. The experimental and quantum chemical explorations of this reaction suggest a mechanism that involves Ir(III)-catalyzed triplet energy transfer followed by a ring-opening reaction ultimately leading to the formation of azomethine ylide intermediates. These azomethine intermediates undergo sequential protonation/copper(I) acetylide addition to provide the products.

Anticancer, anti-inflammatory and analgesic activities of aminoalcohol-based quinoxaline small molecules

ABSTRACT Purpose: Bioactive molecules are relevant to fight cancer and associated conditions. Quinoxaline is a privileged N-heterocycle, notably as anticancer agents. Herein, we report the evaluation of the quinoxaline derivatives DEQX and OAQX as anticancer agents, as well as in function of their anti-inflammatory and analgesic activities. Methods: Quinoxalines were synthesized and tested as anticancer agents based on cell viability and Annexin V-FITC apoptosis. Anti-inflammatory activity was evaluated from mouse carrageenan peritonitis and levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-alfa for enzyme-linked immunosorbent assay. Hot-plate and acetic acid-induced writing test were employed to investigate analgesia. Results: Both reduced the Ht-29 cell viability in a dependent-concentration manner (p < 0.001). Total apoptosis was detected for cells treated with 12.5 and 25 µg/mL of both the compounds for 24 and 48 h (all doses, p < 0.0001). DEQX (all doses, p < 0.01) and OAQX (all doses, p < 0.001) acted in leukocyte migration and decreased the IL-1β and TNF-β levels (p < 0.05). DEQX (all doses, p < 0.05) and OAQX (5mg/kg, p < 0.001) showed peripheral analgesic effect. Conclusions: In-vitro and in-vivo results suggest that these quinoxalines are promising for application in pharmacological area due to their anticancer, anti-inflammatory, and peripheric analgesia.

Novel Substituted Azoloazines with Anticoagulant Activity.

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction.

New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights.

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost-effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor.

An iodine-mediated one-pot synthesis of pyrrolo/indolo [1,2-a]quinoxalines and quinazolin-4-one via utilizing epoxides as alkyl precursors under metal-free conditions has been described. Both 1-(2-aminophenyl)-pyrrole and 2-aminobenzamide could be applied to this protocol. A total of 33 desired products were obtained with moderate to good yields. This methodology was suitable for wide-scale preparation and the obtained products could be further modified into promising pharmaceutically active reagents.

Quinoxaline derivatives as attractive electron-transporting materials.

This review article provides a comprehensive overview of recent advancements in electron transport materials derived from quinoxaline, along with their applications in various electronic devices. We focus on their utilization in organic solar cells (OSCs), dye-sensitized solar cells (DSSCs), organic field-effect transistors (OFETs), organic-light emitting diodes (OLEDs) and other organic electronic technologies. Notably, the potential of quinoxaline derivatives as non-fullerene acceptors in OSCs, auxiliary acceptors and bridging materials in DSSCs, and n-type semiconductors in transistor devices is discussed in detail. Additionally, their significance as thermally activated delayed fluorescence emitters and chromophores for OLEDs, sensors and electrochromic devices is explored. The review emphasizes the remarkable characteristics and versatility of quinoxaline derivatives in electron transport applications. Furthermore, ongoing research efforts aimed at enhancing their performance and addressing key challenges in various applications are presented.

Multi-residue determination of five quinoxalines and three their metabolites in poultry feathers and its application for depletions of olaquindox and quincetone in chickens.

A method for the simultaneous determination of eight quinoxalines and their metabolites in poultry feathers was developed in this study using ultra-performance liquid chromatography combine with quadrupole linear ion trap electrostatic field orbit trap high resolution mass spectrometer. Specificity, matrix effect, linearity, trueness, repeatability, reproducibility, and stability using the Commission of the European Communities, Regulation (EU) 2021/808. The correlation coefficients were all greater than 0.99. The average recoveries of the eight compounds ranged from 76.1% to 112.8%, with coefficient of variation of less than 15%. The limits of detection and quantification of the method were 0.04-0.1 µg/kg and 0.12-0.3 µg/kg, respectively. The method has been successfully applied to depletions of olaquindox and quincetone in feathers of laying hens. Methylquinoxaline-2-carboxylic acid and quincetone are the main metabolites in olaquindox and quincetone in feather, respectively.

Synthesis of Functionalized 3H-pyrrolo-[1,2,3-de] Quinoxalines via Gold-Catalyzed Intramolecular Hydroamination of Alkynes.

A gold-catalyzed protocol to obtain functionalized 3H-pyrrolo [1,2,3-de] quinoxalines from suitable substituted N-alkynyl indoles has been proposed. The mild reaction conditions were revealed to be compatible with different functional groups, including halogen, alkoxyl, cyano, ketone, and ester, allowing the isolation of title compounds with yields from good to high. A reaction mechanism has been proposed, and theoretical calculations have been provided to rationalize the final step of the hypothesized reaction mechanism. As quinoxaline-containing polycyclic compounds, this class of molecules may represent a valuable template in medicinal chemistry and material science.

Bis[2-(thio-phen-2-yl)quinoxaline-κN4]silver(I) perchlorate.

The crystal of the title salt, [Ag(C12H8N2S)2]ClO4, has C2/c symmetry whereby the silver(I) atom sits on a twofold rotation axis, as does the perchlorate anion, which is disordered about this axis. The thienylquinoxaline ligand is nearly planar with the thienyl ring making a dihedral angle of 10.88 (8)° with respect to the quinoxaline moiety.

Photoinduced Synthesis of Bisphosphinated Quinoxalines via Radical Cyclization of o-Diisocyanoarenes with Diphosphines.

The cycloaddition reaction of o-diisocyanoarenes with interelement compounds under light is a very important reaction system to clarify whether this reaction proceeds by radical cyclization or by aza-Bergman cyclization. In this study, a series of diphosphines with phosphorus-phosphorus single bonds were selected as interelement compounds, and their cycloaddition reactions with o-diisocyanoarenes under light were investigated in detail to achieve a novel photoinduced synthesis of bisphosphinated quinoxalines via the radical cyclization pathway. In addition, the photoinduced reaction of diphosphines with isocyanides having o-functional groups such as cyano and ethenyl groups allowed us to elucidate the reaction pathway and product selectivity of this bisphosphination. Furthermore, the one-pot synthesis of PdII -quinoxaline complex was successfully achieved by applying the developed reaction.

Substrate-Controlled Product Divergence in Iron(III)-Catalyzed Reactions of Propargylic Alcohols: Easy Access to Spiro-indenyl 1,4-Benzoxazines and 2-(2,2-Diarylvinyl)quinoxalines.

We report herein unprecedented cascade reactions of O-propargyl-N-tosyl-amino phenols with 10 mol% FeCl3 in DCE at room temperature for 0.67-3 h to form spiro-indenyl 1,4-benzoxazines with 38-89 % yield. Replacing the substrates' oxygen atom by a N-tosylimine group followed by treatment with the same catalyst and solvent at 80 °C produced 2-(2,2-diarylvinyl)quinoxalines in 12-20 h with up to 62 % yield. Mechanistic understanding provided an insight into the transformations. The use of simple substrates and an environmentally benign low-cost catalyst, broad substrate scope and tolerance of diverse functional groups makes the methodology inherently attractive.

Organometallic Platinum(II) Photosensitisers that Demonstrate Ligand-Modulated Triplet-Triplet Annihilation Energy Upconversion Efficiencies.

A series of 2-phenylquinoxaline ligands have been synthesised that introduce either CF3 or OCF3 electron-withdrawing groups at different positions of the phenyl ring. These ligands were investigated as cyclometalating reagents for platinum(II) to give neutral complexes of the form [Pt(C^N)(acac)] (in which C^N=cyclometalating ligand; acac=acetyl acetonate). X-ray crystallographic studies on three examples showed that the complexes adopt an approximate square planar geometry. All examples revealed strong Pt-Pt linear contacts of 3.2041(6), 3.2199(3) and 3.2586(2) Å. The highly coloured complexes display efficient visible absorption at 400-500 nm (ϵ ≈5000 M-1  cm-1 ) and orange red photoluminescent characteristics (λem =603-620 nm; Φem ≤37 %), which were subtly tuned by the ligand. Triplet emitting character was confirmed by microsecond luminescence lifetimes and the photogeneration of singlet oxygen with quantum efficiencies up to 57 %. Each complex was investigated as a photosensitiser for triplet-triplet annihilation energy upconversion using 9,10-diphenylanthracene as the annihilator species: a range of good upconversion efficiencies (ΦUC 5.9-14.1 %) were observed and shown to be strongly influenced by the ligand structure in each case.

Recent advances in transition metal-catalyzed reactions of chloroquinoxalines: Applications in bioorganic chemistry.

The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of metal and transition metal-catalyzed transformations including Sonogashira, Suzuki, Heck type of cross-coupling reactions. The transition metals e.g., Pd, Cu, Fe and Nb catalysts played a key role in these transformations for the construction of various CX (e.g., CC, CN, CO, CS, CP, CSe, etc) bonds. These approaches can be classified based on the catalyst employed, type of the reaction performed and nature of CX bond formation during the reaction. Several of these resultant quinoxaline derivatives have shown diverse biological activities which include apoptosis inducing activities, SIRT1 inhibition, inhibition of luciferace enzyme, antibacterial and antifungal activities, cytotoxicity towards cancer cells, inhibition of PDE4 (phosphodiesterase 4), potential uses against COVID-19, etc. Notably, a review article covering the literature based on transition metal-catalyzed reactions of chloroquinoxalines at the same time summarizing the relevant biological activities of resultant products is rather uncommon. Therefore, an attempt is made in the current review article to summarize (i) the recent advances noted in the transition metal-catalyzed reactions of chloroquinoxalines (ii) with the relevant mechanistic discussions (iii) along with the in vitro, and in silico biological studies (wherever reported) (iv) including Structure-Activity Relationship (SAR) within the particular series of the products reported between 2010 and 2022.

A Convenient Way to Quinoxaline Derivatives through the Reaction of 2-(3-Oxoindolin-2-yl)-2-phenylacetonitriles with Benzene-1,2-diamines.

Microwave-assisted reaction between 2-(3-oxoindolin-2-yl)-2-phenylacetonitriles andbenzene-1,2-diamines leads to the high-yielding formation of the corresponding quinoxalines as sole, easily isolaable products. The featured transformation involves unusual extrusion of phenylacetonitrile molecule and could be performed in a short sequence starting from commonly available indoles and nitroolefins.

Successive Cleavage and Reconstruction of Lignin ß-O-4 Models and Polymer to Access Quinoxalines.

The construction of N-heterocyclic compounds from lignin remains a great challenge due to the complex lignin structure and the involvement of multiple steps, including the cleavage of lignin C-O linkages and the formation of heterocyclic aromatic rings. Herein, the first example of KOH mediated sustainable synthesis of quinoxaline derivatives from lignin ß-O-4 model compounds in a one-pot fashion under transition-metal-free conditions has been achieved. Mechanistic studies suggested that this transformation includes highly coupled cascade steps of cleavage of C-O bonds, dehydrative condensation, sp3 C-H bond oxidative activation, and intramolecular dehydrative coupling reaction. With this protocol, a wide range of functionalized quinoxalines, including an important drug compound AG1295, were synthesized from lignin ß-O-4 model compounds and ß-O-4 polymer, showcasing the application potential of lignin in pharmaceutical synthesis.

Design, Synthesis, and Molecular Docking Studies of Some New Quinoxaline Derivatives as EGFR Targeting Agents.

The synthesis of some new quinoxaline derivatives (IVa-n) and their structure determination using 1H NMR, 13C NMR and mass spectral analysis was described herein. The in vitro anti-cancer activity of the these compounds (IVa-n) revealed that the compound1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVd) has shown promising activity, whereas, compounds 1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVa), 1-(tetrazolo[1,5-a]quinoxalin-4-yl)-2-((1-(m-tolyl)-1H-1,2,3-triazol-4-yl)methyl)pyrazolidine-3,5-dione (IVb), 1-((1-(3,5-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVh) and 1-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVi) exhibited good to moderate activity against four human cancer cell lines such as HeLa, MCF-7, HEK 293T, and A549 as compared to the doxorubicin. Predominantly, the compound displayed excellent activity over HeLa, MCF-7, HEK 293T, and A549 with IC50 values of 3.20 ± 1.32, 4.19 ± 1.87, 3.59 ± 1.34, and 5.29 ± 1.34 µM, respectively. Moreover, molecular docking studies of derivatives (IVa-n) on EGFR receptor suggested that the most potent compound strongly binds to protein EGFR (pdbid:4HJO) and the energy calculations of in silico studies were also in good agreement with the obtained IC50 values. Supplementary Information: The online version contains supplementary material available at 10.1134/S1068162022030220.

New quinoxalin-2(1H)-one-derived VEGFR-2 inhibitors: Design, synthesis, in vitro anticancer evaluations, in silico ADMET, and docking studies.

More than 70% of cancer patients who are treated with chemotherapeutics do not show a durable response. As part of the global plan seeking new effective chemotherapeutics, here, we report the synthesis and in vitro and computational studies of new lenvatinib and sorafenib analog quinoxalines as vascular endothelial growth factor receptor II (VEGFR-2) tyrosine kinase inhibitors. The central quinolone and pyridine moieties of the Food and Drug Administration-approved anticancer agents lenvatinib and sorafenib were replaced with the versatile quinoxaline scaffold that has been exploited for developing potent cytotoxic agents. With some minor structural optimizations, all the other pharmacophoric features of lenvatinib and sorafenib were maintained. Accordingly, three new sets of quinoxalines were synthesized to evaluate their activity against liver, colorectal, and breast malignancies. The results obtained in the in vitro cytotoxicity evaluation study revealed the superior activity of three derivatives (20, 25, and 29) compared with that of doxorubicin and sorafenib. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling and docking of 20, 25, and 29 into the VEGFR-2 receptor were also performed. Results of in silico studies showed the potential of the designed compounds to bind effectively with a number of key residues. The obtained in vitro cytotoxic activity and ADMET profiles of compounds 20, 25, and 29 suggested that they should be subjected to further structural optimizations to develop new candidates in cancer treatment protocols.

Green Synthesis of Indeno[1,2-b]quinoxalines Using ß-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 ß-cyclodextrin (ß-CD) as the supramolecular catalyst. The reaction can be carried out in water and in a solid state at room temperature. ß-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 ß-CD can be recovered and reused without the loss of activity.