[1,2,4]triazolo[4,3-a]quinoxaline as Novel Scaffold in the Imiqualines Family: Candidates with Cytotoxic Activities on Melanoma Cell Lines.

Cutaneous melanoma is one of the most aggressive human cancers and is the deadliest form of skin cancer, essentially due to metastases. Novel therapies are always required, since cutaneous melanoma develop resistance to oncogenic pathway inhibition treatment. The Imiqualine family is composed of heterocycles diversely substituted around imidazo[1,2-a]quinoxaline, imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline scaffolds, which display interesting activities on a panel of cancer cell lines, especially melanoma cell lines. We have designed and prepared novel compounds based on the [1,2,4]triazolo[4,3-a]quinoxaline scaffold through a common synthetic route, using 1-chloro-2-hydrazinoquinoxaline and an appropriate aldehyde. Cyclization is ensured by an oxidation-reduction mechanism using chloranil. The substituents on positions 1 and 8 were chosen based on previous structure-activity relationship (SAR) studies conducted within our heterocyclic Imiqualine family. Physicochemical parameters of all compounds have also been predicted. A375 melanoma cell line viability has been evaluated for 16 compounds. Among them, three novel [1,2,4]triazolo[4,3-a]quinoxalines display cytotoxic activities. Compounds 16a and 16b demonstrate relative activities in the micromolar range (respectively, 3158 nM and 3527 nM). Compound 17a shows the best EC50 of the novel series (365 nM), even if EAPB02303 remains the lead of the entire Imiqualine family (3 nM).

Intramolecular Cyclization of Azido-Isocyanides Triggered by the Azide Anion: An Experimental and Computational Study.

This work describes the unprecedented intramolecular cyclization occurring in a set of α-azido-ω-isocyanides in the presence of catalytic amounts of sodium azide. These species yield the tricyclic cyanamides [1,2,3]triazolo[1,5-a]quinoxaline-5(4H)-carbonitriles, whereas in the presence of an excess of the same reagent, the azido-isocyanides convert into the respective C-substituted tetrazoles through a [3 + 2] cycloaddition between the cyano group of the intermediate cyanamides and the azide anion. The formation of tricyclic cyanamides has been examined by experimental and computational means. The computational study discloses the intermediacy of a long-lived N-cyanoamide anion, detected by NMR monitoring of the experiments, subsequently converting into the final cyanamide in the rate-determining step. The chemical behavior of these azido-isocyanides endowed with an aryl-triazolyl linker has been compared with that of a structurally identical azido-cyanide isomer, experiencing a conventional intramolecular [3 + 2] cycloaddition between its azido and cyanide functionalities. The synthetic procedures described herein constitute metal-free approaches to novel complex heterocyclic systems, such as [1,2,3]triazolo[1,5-a]quinoxalines and 9H-benzo[f]tetrazolo[1,5-d][1,2,3]triazolo[1,5-a][1,4]diazepines.

Exploring the chemical space of functionalized [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the bromodomain of BRD9.

Here we report a detailed structure-activity relationship (SAR) study related to [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the reader module of bromodomain containing-protein 9 (BRD9). 3D structure-based pharmacophore models, previously introduced by us, were here employed to evaluate a second generation of compounds, exploring different substitution patterns on the heterocyclic core. Starting from the promising data obtained from our previously identified [1,2,4]triazolo[4,3-a]quinoxaline-based compounds 1-4, the combination of in silico studies, chemical synthesis, biophysical and in vitro assays led to the identification of a new set of derivatives, selected for thoroughly exploring the chemical space of the bromodomain binding site. In more details, the investigation of different linkers at C-4 position highlighted the amine spacer as mandatory for the binding with the protein counterpart and the crucial role of the alkyl substituents at C-1 for increasing the selectivity toward BRD9. Additionally, the importance of a hydrogen bond donor group, critical to anchor the ZA region and required for the interaction with Ile53 residue, was inferred from the analysis of our collected results. Herein we also propose an optimization and an update of our previously reported "pharm-druglike2" 3D structure-based pharmacophore model, introducing it as "pharm-druglike2.1". Compounds 24-26, 32, 34 and 36 were identified as new valuable BRD9 binders featuring IC50 values in the low micromolar range. Among them, 24 and 36 displayed an excellent selectivity towards BRD9 and a good antiproliferative effect on a panel of leukemia models, especially toward CCRF-CEM cell line, with no cytotoxicity on healthy cells. Notably, the interaction of 24 and 36 with the bromodomain and PHD finger-containing protein 1 (BRPF1) also emerged, disclosing them as new and unexplored dual inhibitors for these two proteins highly involved in leukemia. These findings highlight the potential for the identification of new attractive dual epidrugs as well as a promising starting point for the development of chemical degraders endowed with anticancer activities.

Synthesis, virtual screening and computational approach of a quinoxaline derivative as potent anti-HIV agent targeting the reverse transcriptase enzyme.

Infection by the human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to the appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents that are more active, less toxic, and with increased tolerability to mutations. Quinoxaline derivatives are a class of heterocyclic compounds with a wide range of organic and remedial applications. In addition, they are known to significantly inhibit HIV reverse transcriptase (RT) and HIV replication in cell cultures. For these reasons, we are investigating the synthesis and computational studies of quinoxaline derivatives with a focus on their effects on the HIV RT enzyme, and we present here the structure of one such molecule, methyl 2-[(2E)-3-oxo-1,2,3,4-tetrahydroquinoalin-2-ylidene] acetate, which was confirmed by X-ray diffraction studies. In the crystal, N-H···O and C-H···O hydrogen bonds form ribbons whose mean planes are inclined to (111) by 25.69(8)°. The ribbons are formed into stacks by C-H···π(ring) interactions and π-stacking interactions between carbonyl groups. The Hirshfeld surface map allows us to understand the nature of interactions in the contribution to crystal packing. A density functional theory (DFT) calculation was performed to optimize the geometrical parameters and then they were compared with the solid-state phase. The molecular electrostatic potential map displays reactive sites on the surface, which are responsible for intermolecular interaction in the chemical species. Computational molecular docking, in addition to molecular dynamics simulations and MMGB/PBSA binding energy techniques, was used to assess the affinity of the molecule for the HIV reverse transcriptase enzyme. The new quinoxaline derivative is more powerful in terms of binding affinity and binding conformation stability with the HIV reverse transcriptase enzyme, which suggests the molecule is a good candidate for further biological optimization.Communicated by Ramaswamy H. Sarma.

Design, synthesis, and pharmacological evaluations of pyrrolo[1,2-a]quinoxaline-based derivatives as potent and selective sirt6 activators.

Sirt6 activation has emerged as a promising drug target for the treatment of various human diseases, while only limited Sirt6 activators have been reported. Herein, a series of novel pyrrolo[1,2-a]quinoxaline-based derivatives have been identified as potent and selective Sirt6 activators with low cytotoxicity. Sirt6-knockdown findings have validated the on-target effects of this class of Sirt6 activators. Docking studies indicate the protonated nitrogen on the side chain of 38 forms π-cation interactions with Trp188, further stabilizing it into this extended binding pocket. New compounds 35, 36, 38, 46, 47, and 50 strongly repressed LPS-induced proinflammatory cytokine/chemokine production, while 38 also significantly suppressed SARS-CoV-2 infection with an EC50 value of 9.3 µM. Moreover, compound 36 significantly inhibited the colony formation of cancer cells. These new molecules may serve as useful pharmacological tools or potential therapeutics against cancer, inflammation, and infectious diseases.

Construction of Spirocyclic Pyrrolo[1,2-a]quinoxalines via Palladium-Catalyzed Hydrogenative Coupling of Phenols and Nitroarenes.

The replacement of fossil resources with biomass resources in the construction of N-heterocycles is rapidly attracting research interest. Herein, we report palladium-catalyzed selective hydrogenative coupling of nitroarenes and phenols based on a transfer hydrogenation strategy, allowing straightforward access to spirocyclic pyrrolo- and indolo-fused quinoxalines, a class of compounds found in numerous natural alkaloids. The synthetic protocol is characterized by a broad substrate scope and the utilization of biomass-derived reactants and commercially available catalysts. In such transformations, high-pressure and explosive hydrogen are not required. This report provides a new protocol for converting biomass-derived phenols into value-added nitrogen-containing chemicals.

Cobalt-Catalyzed Effective Access to Quinoxalines with Insights in Annulation of Terminal Alkynes and o-Phenylenediamines.

A novel methodology for the annulation of terminal alkynes and o-phenylenediamines by using a combination of a cobalt catalyst and oxygen as a terminal oxidant is reported. This method shows wide substrate scope and good functional group tolerance and provides a wide range of quinoxalines in good to high yields. The method is demonstrated by its gram-scale and broad potential applications. Furthermore, this protocol serves as a powerful tool for the late-stage functionalization of various complex bioactive molecules and drugs to provide a new class of molecules containing two distinct bioactive molecules directly linked. Detailed mechanistic studies reveal that the current reaction goes through a novel mechanism different from the previously reported glyoxal mechanism.

In Vitro and In Silico Analysis of New n-Butyl and Isobutyl Quinoxaline-7-carboxylate 1,4-di-N-oxide Derivatives against Trypanosoma cruzi as Trypanothione Reductase Inhibitors.

American trypanosomiasis is a worldwide health problem that requires attention due to ineffective treatment options. We evaluated n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives against trypomastigotes of the Trypanosoma cruzi strains NINOA and INC-5. An in silico analysis of the interactions of 1,4-di-N-oxide on the active site of trypanothione reductase (TR) and an enzyme inhibition study was carried out. The n-butyl series compound identified as T-150 had the best trypanocidal activity against T. cruzi trypomastigotes, with a 13% TR inhibition at 44 µM. The derivative T-147 behaved as a mixed inhibitor with Ki and Ki' inhibition constants of 11.4 and 60.8 µM, respectively. This finding is comparable to the TR inhibitor mepacrine (Ki = 19 µM).

Electro-oxidation induced O-S cross-coupling of quinoxalinones with sodium sulfinates for synthesizing 2-sulfonyloxylated quinoxalines.

The functionalization of quinoxalinones is synthetically and biologically appealing, however, C2 functionalized quinoxalinones is not reported via environmentally friendly approach. Herein, we disclosed C2-O sulfonylation of quinoxalinones via our developed electrochemical oxidative O-S coupling strategy for synthesizing 2-sulfonyloxylated quinoxalines. Applying this protocol, quinoxalin-ones and sodium sulfinates as the starting materials, a wide range of 2-sulfonyloxyl quinoxaline derivatives were obtained in moderate to good yields with good functional-group tolerance under mild conditions without additional oxidants. The utility of this methodology and the sulfonyloxyl handles was demonstrated trough gram-scale preparation and the synthesis of 2-substituted quinoxaline-based bioactive molecules, respectively.

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.

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies.

Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35-8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.

Effect of Acrolein, a Lipid Oxidation Product, on the Formation of the Heterocyclic Aromatic Amine 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in Model Systems and Roast Salmon Patties.

The effect of acrolein, a lipid oxidation product, on the formation of the heterocyclic aromatic amine 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in a chemical model containing glycine, creatinine, and glucose. Acrolein addition at 0.02-0.2 mmol increased MeIQx formation, while high levels of acrolein (>0.2 mmol) did not further increase MeIQx formation. Moreover, acrolein addition decreased the residue of glycine and creatinine but increased the residue of glucose; it also increased the formation of volatile intermediates in the MeIQx-producing chemical model. Further analysis indicated that acrolein can react with glycine, creatinine, and MeIQx to eliminate them. These results revealed that acrolein was able to contribute to MeIQx formation as a consequence of the comprehensive ability of acrolein to facilitate Strecker degradation of glycine, increase the formation of volatile intermediates, and react with glycine, creatinine, and MeIQx. In addition, the oxidation of minced salmon increased the content of MeIQx in the roasted salmon patties, further supporting the potential contribution role of lipid oxidation products in the formation of MeIQx.

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

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

Naked Eye Chemosensor and In Vivo Chelating Activity of Iron (III) By Bromopyridine Quinoxaline (BPQ).

A wide variety of medical, biomedical, and industrial applications has been reported for quinoxalines derivatives. In this work, a novel quinoxaline derivative was designed and synthesized. Naked-eye and quantitative detection of Fe3+ among several cations were evaluated using UV-Vis spectroscopy. New chemosensor, 2,3-bis(6-bromopyridine-2-yl)-6-chloroquinoxaline named BPQ, showed a selective interaction for iron ion over other tested cations by changing color. Iron overloaded mice were prepared as a thalassemia model and then the effects of iron-chelating activities of BPQ were experienced. The job's plot methods determined the stoichiometric ratio of ligand to Fe3+ (1:1). The iron content in serum was evaluated by atomic absorption spectroscopy (AAS). Results showed significant differences (two-fold decrease in total iron and Fe3+) between the iron overloaded and BPQ (dose of 20 mgkg-1). The BPQ was identified as a ligand, which can be applied as a new chelator for decreasing the excess iron of blood.

An appraisal on synthetic and pharmaceutical perspectives of quinoxaline 1,4-di-N-oxide scaffold.

Quinoxaline 1,4-di-N-oxides (QdNOs) exhibit multifaceted biological properties, wherein antimicrobial, anticancer, antitrypanosomal, and anti-inflammatory properties are included. Because of their various activities in clinical practice and research, they have a wide spectrum of uses and possibilities. QdNOs have received a significant amount of attention, and research into their medicinal chemistry is still a part of experimental investigation and analytical studies. In this review, QdNOs are classified depending on their actions, which include antibacterial and anti-mycobacterial, anticancer or antitumor, antimalarial, antifungal, and other activities. In a conclusion, it's important to base the development of novel synthetic techniques and the design of new QdNO derivatives on the most up-to-date knowledge gleaned from recent research. With the summarised structure-activity relationship of fascinating QdNOs, this review aims to provide insights into the developments in the chemistry and biological activity of QdNO derivatives.

Copper-Catalyzed Oxidative [3 + 2]-Annulation of Quinoxalin-2(1H)-one with Oxime Esters toward Functionalized Pyrazolo[1,5-a]quinoxalin-4(5H)-ones as Opioid Receptor Modulators.

Pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives as novel opioid receptor modulators have been synthesized via copper-catalyzed oxidative [3 + 2]-annulation of quinoxalin-2(1H)-one and oxime-O-acetates. This hydrazine-free C-C and N-N bond formation strategy starts with the generation of C2N1 synthon using oxime acetate, which reacts in a [3 + 2] manner with quinoxalin-2(1H)-one, followed by oxidative aromatization. The synthesized compounds were tested against opioid receptors, of which eight compounds exhibited an antagonistic effect with EC50 < 5 µM at various opioid receptors. Molecular docking studies were performed to identify the binding of active pyrazolo[1,5-a]quinoxalin-4(5H)-one ligands with hKOR protein. Docking results indicated that compounds 3d and 3g participate in hydrogen bonding with the hydroxyl group of T111 of the active site pocket residue.

Synthesis, Molecular Docking, and 2D-QSAR Modeling of Quinoxaline Derivatives as Potent Anticancer Agents against Triple-negative Breast Cancer.

BACKGROUND: Breast carcinomas aka triple-negative breast cancers (TNBC) are one of the most complex and aggressive forms of cancers in females. Recently, studies have shown that these carcinomas are resistant to hormone-targeted therapies, which makes it a priority to search for effective and potential anticancer drugs. The present study aimed to synthesize and develop the 2Dquantitative structural activity relationship model (QSAR) of quinoxaline derivatives as a potential anticancer agent. METHODS: Quinoxaline derivatives were designed and synthesized (8a-8i and 9a-9d) and the 2DQSAR model against TNBC was developed using VLife MDS v4.4. The anticancer activity was investigated against the TNBC MDA-MB-231 cell line using an MTT cytotoxicity assay. Molecular docking studies along with the estimation of ADMET parameters were done using Discovery Studio. The most potent compound was docked against the ß-tubulin protein target (PDB: 4O2B), using the Autodock Vina v0.8 program. RESULTS: Eleven derivatives of quinoxaline were designed and synthesized (8a-8i and 9a-9d) and a 2D-QSAR model was developed against the TNBC MDA-MB231 cell line. The regression coefficient values for the training set were (r2) 0.78 and (q2) 0.71. Further, external test set regression (pred_r2) was 0.68. Five molecular descriptors viz., energy dispersive (Epsilon3), protein-coding gene (T_T_C_6), molecular force field (MMFF_6), most hydrophobic hydrophilic distance (XA), and Zcomp Dipole were identified. After ADMET, the best analog 8a showed the best activity against the TNBC cell line. The best-predicted hit '8a' was found to bind within the active site of the ß- tubulin protein target. CONCLUSION: The newly synthesized quinoxaline compounds could serve as potent leads for the development of novel anti-cancer agents against TNBC.

Quinoxaline based unfused non-fullerene acceptor molecules with PTB7-Th donor polymer for high performance organic solar cell applications.

Unfused non-fullerene acceptors possess advantages such as simplicity of synthesis, low toxicity, high yield with less manufacturing cost. In the present era, the rapid emergence of new unfused acceptors with high yields and stability is an urgent need. This report has developed four new fullerene-free quinoxaline-based unfused acceptor molecules (QX1 to QX4) for high-performance organic solar cell applications. All designed molecules have a long conjugating backbone which facilitates easy charge transportation between donor and acceptor ends. Different physiochemical, optoelectrical, and photovoltaic properties of designed molecules have been explored through density functional theory (DFT), and time-density functional theory (TD-DFT). A significant reduction in energy bandgap with red-shifting in absorption spectrum was noted for QX1 to QX4. Further, QX1 to QX4 exhibited good values of open-circuit voltage with low excitation and binding energies. Transition density matrix (TDM) analysis was also performed to explore the charge transfer behavior in the designed molecule. In addition, QX1 to QX4 expressed high mobility of electrons and holes with high molecular orbitals contributions. Outcomes of different geometric parameters suggested that QX1 to QX4 are excellent acceptor molecules (when blended with PTB7-Th polymer) for the active layer of organic solar cells.