Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

The fungicidal effectiveness of 2-Chloro-3-hydrazinylquinoxaline, a newly developed quinoxaline derivative, against Candida species.

BACKGROUND: Candida represents a prevalent fungal infection, notable for its substantial implications on morbidity and mortality rates. In the landscape of prospective treatments, quinoxaline derivatives emerge as a category of compact compounds exhibiting notable potential in addressing infections. These derivatives showcase promising antimicrobial efficacy coupled with favorable pharmacokinetic and safety characteristics. AIMS: The central aim of this investigation was to examine the antifungal characteristics of 2-Chloro-3-hydrazinylquinoxaline against diverse strains of Candida and Aspergillus in vitro. Additionally, we endeavored to assess the in vivo efficacy of 2-Chloro-3-hydrazinylquinoxaline using a murine model for oral candidiasis induced by C. albicans cells ATCC 10231. RESULTS: 2-Chloro-3-hydrazinylquinoxaline demonstrated noteworthy effectiveness when tested against various reference strains of Candida species. It exhibited heightened efficacy, particularly against Candida krusei isolates. However, its performance against Candida albicans, Candida tropicalis, Candida glabrata, Candida parapsilosis, and Candida auris isolates exhibited variability. Notably, 2-Chloro-3-hydrazinylquinoxaline manifests variable efficacy against Aspergillus fumigatus, Aspergillus niger, Aspergillus terreus and Aspergillus flavus and no effect against Aspergillus brasiliensis. In a murine model, 2-Chloro-3-hydrazinylquinoxaline exhibited significant efficacy in combating the C. albicans cells ATCC 10231 strain, underscoring its potential as a viable treatment option. CONCLUSION: 2-Chloro-3-hydrazinylquinoxaline has demonstrated substantial potential in effectively addressing various Candida and Aspergillus species, showcasing dual attributes of antifungal and anti-inflammatory properties. However, to attain a more comprehensive understanding of its therapeutic capabilities, further investigations, incorporating additional tests and experiments, are imperative.

Semiconducting Polymers Based on Asymmetric Thiadiazoloquinoxaline for Augmented In Vivo NIR-II Photoacoustic Imaging.

A photoacoustic (PA) imaging technique using the second near-infrared (NIR-II) window has attracted more and more attention because of its merits of deeper penetration depth and higher signal-to-noise (S/N) ratio than that using the first near-infrared (NIR-I) one. However, the design and development of high-performance PA imaging contrast agents in the NIR-II window is still a challenge. A semiconducting polymer, constructed by asymmetric units, exhibits regiorandom characteristics that effectively increase the distortion of the backbone. This increase in the degree of twist can regulate the twisted intramolecular charge transfer (TICT) effect, resulting in an enhancement of the PA signal. In this paper, an asymmetric structural acceptor strategy is developed to improve the PA signals of the resulting semiconducting polymer (PATQ-MP) in the NIR-II window with improved brightness, higher S/N ratio, and better photothermal conversion efficiency compared to polymers with the same main-chain structure containing a symmetric acceptor. DFT analysis showed that PATQ-MP containing an asymmetric acceptor monomer had a larger dihedral angle, which effectively improved the PA signal intensity by enhancing the TICT effect. The PEG-encapsulated PATQ-MP nanoparticles exhibit promising performance in the PA imaging of mouse tumors in vivo, demonstrating the clear identification of microvessels as small as 100 µm along with rapid metabolism within a span of 5 h. Therefore, this work provides a unique molecular design strategy for improving the signal intensity of PA imaging in the NIR-II window.

Inhibition of protein misfolding and aggregation by steroidal quinoxalin-2(1H)-one and their molecular docking studies.

A series of D-ring fused 16-substituted steroidal quinoxalin-2(1H)-one attached to an electron-releasing (ER) or electron-withdrawing (EW) groups via steroidal oxoacetate intermediate were synthesized to investigate their protein aggregation inhibition potential using human lysozyme (HLZ). The influence of the type of substituent at the C-6 positions of the quinoxalin-2(1H)-one ring on the protein aggregation inhibition potential was observed, showing that the EW moiety improved the protein aggregation inhibition potency. Of all the evaluated compounds, NO2-substituted quinoxalin-2(1H)-one derivative 13 was the most active compound and had a maximum protein aggregation inhibition effect. Significant stabilization effects strongly support the binding of the most biologically active steroidal quinoxalin-2(1H)-one with docking studies. The predicted physicochemical and ADME properties lie within a drug-like space which shows no violation of Lipinski's rule of five except compounds 12 and 13. Combined, our results suggest that D-ring fused 16-substituted steroidal quinoxalin-2(1H)-one has the potential to modulate the protein aggregation inhibition effect.

Design of Dyes Based on the Quinoline or Quinoxaline Skeleton towards Visible Light Photoinitiators.

Dyes based on quinoline and quinoxaline skeletons were designed for application as visible light photoinitiators. The obtained compounds absorb electromagnetic radiation on the border between ultraviolet and visible light, which allows the use of dental lamps as light sources during the initiation of the photopolymerization reaction. Their another desirable feature is the ability to create a long-lived excited state, which enables the chain reaction to proceed through the mechanism of intermolecular electron transfer. In two-component photoinitiating systems, in the presence of an electron donor or a hydrogen atom donor, the synthesized compounds show excellent abilities to photoinitiate the polymerization of acrylates. In control tests, the efficiency of photopolymerization using modified quinoline and quinoxaline derivatives is comparable to that obtained using a typical, commercial photoinitiator for dentistry, camphorquinone. Moreover, the use of the tested compounds requires a small amount of photoinitiator (only 0.04% by weight) to initiate the reaction. The research also showed a significant acceleration of the photopolymerization process and shortening of the reaction time. In practice, this means that the new two-component initiating systems can be used in much lower concentrations without slowing down the speed of obtaining polymer materials. It is worth emphasizing that these two features of the new initiating system allow for cost reduction by reducing financial outlays on both materials (photoinitiators) and electricity.

Planar-structured thiadiazoloquinoxaline-based NIR-II dye for tumor phototheranostics.

Second near-infrared (NIR-II) fluorescence imaging shows huge application prospects in clinical disease diagnosis and surgical navigation, while it is still a big challenge to exploit high performance NIR-II dyes with long-wavelength absorption and high fluorescence quantum yield. Herein, based on planar π-conjugated donor-acceptor-donor systems, three NIR-II dyes (TP-DBBT, TP-TQ1, and TP-TQ2) were synthesized with bulk steric hindrance, and the influence of acceptor engineering on absorption/emission wavelengths, fluorescence efficiency and photothermal properties was systematically investigated. Compared with TP-DBBT and TP-TQ2, the TP-TQ1 based on 6,7-diphenyl-[1,2,5]thiadiazoloquinoxaline can well balance absorption/emission wavelengths, NIR-II fluorescence brightness and photothermal effects. And the TP-TQ1 nanoparticles (NPs) possess high absorption ability at a peak absorption of 877 nm, with a high relative quantum yield of 0.69% for large steric hindrance hampering the close π-π stacking interactions. Furthermore, the TP-TQ1 NPs show a desirable photothermal conversion efficiency of 48% and good compatibility. In vivo experiments demonstrate that the TP-TQ1 NPs can serve as a versatile theranostic agent for NIR-II fluorescence/photoacoustic imaging-guided tumor phototherapy. The molecular planarization strategy provides an approach for designing efficient NIR-II fluorophores with extending absorption/emission wavelength, high fluorescence brightness, and outstanding phototheranostic performance.

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.

Protocol for stereodivergent asymmetric hydrogenation of quinoxalines.

Chiral 1,2,3,4-tetrahydroquinoxalines are ubiquitous in natural products and bioactive molecules. Herein, we disclose a protocol for stereodivergent asymmetric hydrogenation of disubstituted quinoxalines for the preparation of both cis- and trans-enantioenriched disubstituted tetrahydroquinoxalines (up to >20:1 d.r. and 99% ee). We describe steps for synthesis of ligands and substrate, setup of hydrogenation of disubstituted quinoxalines, and purification of products. Additionally, we provide detailed diagrams of the hydrogenation installation. For complete details on the use and execution of this protocol, please refer to Liu et al.1.

[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.

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).

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.

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.

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.