Benzofuranone Derivatives Research Articles

Asymmetric Intermolecular Conjugate Addition of 3-Substituted 2-Benzofuranones to Maleimides via Noncovalent NHC Catalysis

AbstractAn efficient N-heterocyclic carbene (NHC)-catalyzed asymmetric conjugate addition reaction to afford synthetically challenging benzofuranone derivatives having vicinal all-carbon quaternary and tertiary stereocenters is presented. The reaction operates solely through noncovalent interaction between a newly designed NHC and the substrates, providing access to a series of functionalized benzofuranones in good yields and with high ee values. The protocol applies to preparative-scale synthesis. A catalytic cycle involving a noncovalent substrate–NHC interaction is implicated in the process, based on a mechanistic control study.

Synthesis and Biological Evaluation of 2-Azolylmethylene-3-(2H)-benzofuranone Derivatives as Potent Monoamine Oxidases Inhibitors.

A series of 2-azolylmethylene-3-(2H)-benzofuranone derivatives, 2-indolylmethylene-3-(2H)-benzofuranone and 2-pyrrolylmethylene-3-(2H)-benzofuranone derivatives, were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 1b, 3b, 6b, 7b, and 10b showed strong inhibitory activity against MAO-A, and compound 3b showed the highest potency and selectivity, with an IC50 value of 21 nM and a MAO-A selectivity index of 48. Compounds 3c, 4c, 9a, 9c, 10c, 11a, and 11c showed strong inhibitory activity against MAO-B, and compound 4c showed the highest potency and selectivity, with an IC50 value of 16 nM and a MAO-B selectivity index of >1100. Further analysis of these compounds indicated that compound 3b for MAO-A and compound 4c for MAO-B were competitive inhibitors, with Ki values of 10 and 6.1 nM, respectively. Furthermore, computational analyses, such as quantitative structure-activity relationship (QSAR) analysis of the 2-azolylmethylene-3-(2H)-benzofuranone derivatives conducting their pIC50 values with the Molecular Operating Environment (MOE) and Mordred, and molecular docking analysis using MOE-Dock supported that the 2-azolylmethylene-3-(2H)-benzofuranone derivatives are a privileged scaffold for the design and development of novel MAO inhibitors.

Photochemistry of 2-(2-formylphenyloxy)acetic acid derivatives: synthesis of hydroxychromanones and benzofuranones.

Photochemical transformations of small molecules, such as ortho-substituted benzaldehydes, in the absence of a photocatalyst are significantly underexplored and may reveal unexpected outcomes. In the present paper, we showed that 2-(2-formylphenoxy)acetic acid and its esters undergo photocyclization into chromanone and benzofuranone derivatives under 365 nm irradiation. The reaction occurs exclusively in dimethyl sulfoxide and can be used to efficiently obtain hydroxychromanones in good yields (27-91%). A detailed mechanistic study revealed the clue of the divergent phototransformation with various products.

Electrochemistry of Flavonoids.

This review presents a description of the available data from the literature on the electrochemical properties of flavonoids. The emphasis has been placed on the mechanism of oxidation processes and an attempt was made to find a general relation between the observed reaction paths and the structure of flavonoids. Regardless of the solvent used, three potential regions related to flavonoid structures are characteristic of the occurrence of their electrochemical oxidation. The potential values depend on the solvent used. In the less positive potential region, flavonoids, which have an ortho dihydroxy moiety, are reversibly oxidized to corresponding o-quinones. The o-quinones, if they possess a C3 hydroxyl group, react with water to form a benzofuranone derivative (II). In the second potential region, (II) is irreversibly oxidized. In this potential region, some flavonoids without an ortho dihydroxy moiety can also be oxidized to the corresponding p-quinone methides. The oxidation of the hydroxyl groups located in ring A, which are not in the ortho position, occurs in the third potential region at the most positive values. Some discrepancies in the reported reaction mechanisms have been indicated, and this is a good starting point for further investigations.

Regioselective Radical Cascade Cyclizations of Alkyne-Tethered Cyclohexadienones with Chalcogenides under Visible-Light Catalysis.

Herein, we demonstrated a silver/K2S2O8-mediated highly regio- and diastereoselective 6/5-exo trig radical cascade cyclization of alkyne-tethered cyclohexadienones with sulfonyl hydrazides or sodium sulfinates and subsequent selenation to access 6,6-dihydrochromenone and 6,5-fused tetrahydro benzofuranone derivatives. This reaction protocol features high functional group compatibility and has a wide substrate scope providing a variety of dihydrochromenones and tetrahydro benzofuranone derivatives in good to excellent yields. The reaction proceeds via the attack of a sulfonyl radical to alkyne over the activated Michael acceptor. The TEMPO quenching experiment implies the presence of a radical intermediate. Further synthetic versatility of 6,6- and 5,6-fused derivatives is also showcased.

Hericioic Acids A-G and Hericiofuranoic Acid; Neurotrophic Agents from Cultures of the European Mushroom Hericium flagellum.

Neurodegenerative diseases are currently posing huge social, economic, and healthcare burdens among the aged populations worldwide with few and only palliative treatment alternatives available. Natural products continue to be a source of a vast array of potent neurotrophic molecules that could be considered as drug design starting points. The present study reports eight new isoindolinone and benzofuranone derivatives, for which we propose the trivial names, hericioic acids A-G (1-7) and hericiofuranoic acid (8), which were isolated from a solid culture (using rice as substrate) of the rare European edible mushroom Hericium flagellum. The chemical structures of these compounds were determined based on extensive 1D and 2D NMR spectroscopy along with HRESIMS analyses. The isolated compounds were assessed for their neurotrophic activity in rat pheochromocytoma cells (PC-12) to promote neurite outgrowth on 5 ng NGF supplementation; all the compounds increased neurite outgrowths, with compounds 3, 4, and 8 exhibiting the strongest effects.

Synthesis of benzylidene-benzofuranone derivatives as probes for detection of amyloid fibrils in cells

Aggregated protein is the common cause of a wide variety of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, etc. It is proven that protein aggregation like amyloid β (Aβ) is one of the critical factors causing AD and, its diagnosis in the early stages of the disease is important for the treatment or prevention of AD. To have a better understanding of protein aggregation and its pathologies, there is a huge need to design and develop new and more trustworthy probe molecules for in vitro amyloid quantification and in vivo amyloid imaging. In this study, 17 new biomarker compounds, have been synthesized from benzofuranone derivatives, to detect and identify amyloid in vitro (dye-binding assay) as well as in the cell by staining method. According to the results, some of these synthetic derivatives can be considered suitable identifiers and quantifiers to detect amyloid fibrils in vitro. Compared to thioflavin T, 4 probes out of 17 probes have shown good results in selectivity and detectability of Aβ depositions, and their binding properties were also confirmed with in silico analysis. The drug-likeness prediction results for selected compounds by the Swiss ADME server show a satisfactory percentage of blood-brain barrier (BBB) permeability and gastrointestinal (GI) absorption. Among all of them, compound 10 was able to show better binding properties than others, and in vivo study showed that this compound was capable of detecting intracellular amyloid. Communicated by Ramaswamy H. Sarma

Antileishmanial Activities of (Z)-2-(Nitroimidazolylmethylene)-3(2H)-Benzofuranones: Synthesis, In Vitro Assessment, and Bioactivation by NTR 1 and 2.

The antileishmanial activity of a series of (Z)-2-(heteroarylmethylene)-3(2H)-benzofuranone derivatives, possessing 5-nitroimidazole or 4-nitroimidazole moieties, was investigated against Leishmania major promastigotes and some analogues exhibited prominent activities. Compounds with IC50 values lower than 20 μM were further examined against L. donovani axenic amastigotes. Evaluated analogues in 5-nitroimidazole subgroup demonstrated significantly superior activity (~17-88-folds) against L. donovani in comparison to L. major. (Z)-7-Methoxy-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2H)-benzofuranone (5n) showed the highest L. donovani anti-axenic amastigote activity with IC50 of 0.016 μM. The cytotoxicity of these analogues was determined using PMM peritoneal mouse macrophage and THP-1 human leukemia monocytic cell lines and high selectivity indices of 26 to 431 were obtained for their anti-axenic amastigote effect over the cytotoxicity on PMM cells. Further studies on their mode of action showed that 5-nitroimidazole compounds were bioactivated predominantly by nitroreductase 1 (NTR1) and 4-nitroimidazole analogues by both NTR1 and 2. It is likely that this bioactivation results in the production of nitroso and hydroxylamine metabolites that are cytotoxic for the Leishmania parasite.

Electrochemical Investigation of some Flavonoids in Aprotic Media

AbstractCyclic voltammerty data for the oxidation of 15 flavonoids in acetonitrile have been presented. Up to three peaks in different potential regions appear in the CV curves, depending on the structure of a flavonoid. The peak in the first potential region (+0.79÷+1.03 V vs SCE) occurs when a flavonoid molecule has an o‐dihydroxy moiety in the ring A or B. From the data in the literature, the formation of o‐quinone is responsible for the occurrence of the peak. When the o‐dihydroxy moiety is in ring B and the hydroxyl group is at position 3, the second peak in the potential region+1.08÷+1.32 V, is present. It is an agreement that the peak is due to oxidation of benzofuranone derivative formed in reaction of o‐quinone with water. Molecules with an o‐quinone moiety located in ring A seem to be less reactive, and the peak in the second potential region does not occur. However, the existence of an o‐quinone in the ring B is not necessary for the peak in the second potential region to be present. The oxidation of kaempferol and morin, which have hydroxyl groups at positions 3 and 4’, takes place at 0.98 V and 0.97 V, respectively, and leads to the formation of p‐quinone methide. We have shown that the peak in the second potential region also appears when the hydroxyl group in the flavonoid molecule is only at position 3 or at position 4’. For 3‐hydroxyflavone and apigenin, which are oxidized at +1.10 V and 1.49 V respectively, p‐quinone methide was detected after controlled potential bulk electrolysis. A mechanism which includes the reaction of the carbon radical with a trace of water has been proposed. For flavonoids that have an o‐dihydroxy moiety in ring B and the hydroxyl group at position 3, two oxidation peaks are observed in the CV curves in the second potential region for low scan rates (below 0.1 V s−1). An explanation of this behavior has been proposed.

Sequential Continuous-Flow Synthesis of 3-Aryl Benzofuranones.

A sequential continuous-flow system to produce 3-aryl benzofuranones was developed. Starting from 2,4-di-tert-butylphenol and glyoxylic acid monohydrate, both the initial cyclocondensation and the subsequent Friedel-Crafts alkylation were catalyzed by the same heterogeneous catalyst, Amberlyst-15H. The catalyst has a promising life-time for these two steps, and it was able to be recovered and reused for several runs without deactivation. By using the established flow system, 5,7-di-tert-butyl-3-(3,4-dimethylphenyl)-3H-benzofuran-2-one (Irganox HP-136), which is a commercial antioxidant, was prepared in 88% two-step yield. Reactions with various aromatic compounds proceeded well under flow conditions to afford 3-aryl benzo-furanone derivatives in high yields with good functional group compatibility.

Electrochemistry Investigation of Drugs Encapsulated in Cyclodextrins.

The biological electron transfer reactions play an important role in the bioactivity of drugs; thus, the knowledge of their electrochemical behavior is crucial. The formation of radicals during oxidation or reduction, the presence of short-living intermediates, the determination of reaction mechanisms involving electron and proton transfers, all contribute to the comprehension of drug activities and the determination of their mode of action and their metabolites. In addition, if a drug is encapsulated in the cyclodextrin cavity, its electrochemical properties can change compared to a free drug molecule. Here we describe the combination of cyclic voltammetry, UV-Vis spectroelectrochemistry, GC-MS, HPLC-DAD, and HPLC-MS/MS as techniques for evaluating the oxidation mechanism of a drug encapsulated in the cavity of a cyclodextrin. The cavity of cyclodextrin plays a significant role in increasing the stability of the encapsulated products; therefore the identification of oxidation intermediates as semiquinone and benzofuranone derivatives of quercetin is possible in these conditions. The differences in oxidation potentials of the bioactive flavonol quercetin and its cyclodextrin complex relating to its antioxidant activity and the oxidation mechanism are herein discussed.

Modern approaches to the synthesis of 3-(acylamino)-and 3-(carbamoylamino)benzofuran-2(3H)-ones (microreview)

The microreview examines modern approaches to the synthesis of 3-(acylamino)- and 3-(carbamoylamino) benzofuran-2(3H)-ones described over the past 10 years (2011–2020). The methods are subdivided into groups depending on the used starting reagents and the reactions underlying them. Approaches based on the use of phenols as starting compounds, methods of modification of benzofuranone derivatives, as well as some other methods are considered.

Nonthermal Plasma-Induced Degradation of Morin and Enhancement of Biological Activities.

In the present study, non-thermal dielectric barrier discharge (DBD) plasma of induced structural changes of morin resulted in the isolation of one previously undescribed benzofuranone derivative, along with two known compounds. The chemical structures of these degradation products were elucidated by UV, NMR and FAB-MS spectroscopic analyses. The isolated three compounds showed potent antioxidative activities in two different tests, with IC50 values in the range of 12.9-41.8 μm in the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+ ) radical scavenging activity, 19.0-71.9 μm for hydroxyl radical scavenging activity test. Furthermore, the new methoxylated benzofuranone exhibited enhancement of inhibitory effects against pancreatic lipase with an IC50 value of 90.7±1.6 μm, when compared to the parent morin. These results suggested that the degradation products isolated from plasma exposed morin might be beneficial for prevention of obesity and related diseases.

Synthesis and characterization of high affinity fluorogenic α-synuclein probes.

Fluorescent small molecules are powerful tools for imaging α-synuclein pathology in vitro and in vivo. In this work, we explore benzofuranone as a potential scaffold for the design of fluorescent α-synuclein probes. These compounds have high affinity for α-synuclein, show fluorescent turn-on upon binding to fibrils, and display different binding to Lewy bodies, Lewy neurites and glial cytoplasmic inclusion pathologies in post-mortem brain tissue. These studies not only reveal the potential of benzofuranone compounds as α-synuclein specific fluorescent probes, but also have implications for the ways in which α-synucleinopathies are conformationally different and display distinct small molecule binding sites.

Redox properties of individual quercetin moieties

Quercetin is one of the most prominent and widely studied flavonoids. Its oxidation has been previously investigated only indirectly by comparative analyses of structurally analogous compounds, e.g. dihydroquercetin (taxifolin). To provide direct evidence about the mechanism of quercetin oxidation, we employed selective alkylation procedures for the step-by-step blocking of individual redox active sites, i.e. the catechol, resorcinol and enol C-3 hydroxyls, as represented by newly prepared quercetin derivatives 1–3. Based on the structure-activity relationship (SAR), electrochemical, and computational (density functional theory) studies, we can clearly confirm that quercetin is oxidized in the following steps: the catechol moiety is oxidized first, forming the benzofuranone derivative via intramolecular rearrangement mechanism; therefore the quercetin C-3 hydroxy group cannot be involved in further oxidation reactions or other biochemical processes. The benzofuranone is oxidized subsequently, followed by oxidation of the resorcinol motif to complete the electrochemical cascade of reactions. Derivatization of individual quercetin hydroxyls has a significant effect on its redox behavior, and, importantly, on its antiradical and stability properties, as shown in DPPH/ABTS radical scavenging assays and UV–Vis spectrophotometry, respectively. The SAR data reported here are instrumental for future studies on the oxidation of biologically or technologically important flavonoids and other polyphenols or polyhydroxy substituted aromatics. This is the first complete and direct study mapping redox properties of individual moieties in quercetin structure.

The Purification, Characterization, and Biological Activity of New Polyketides from Mangrove-Derived Endophytic Fungus Epicoccum nigrum SCNU-F0002.

Six new polyketides, including one coumarin (1), two isocoumarins (2 and 3), dihydroradicinin (4), and two benzofuranone derivatives (7 and 8), together with seven known analogues (5–6 and 9–13) were isolated from the culture of the mangrove endophytic fungus Epicoccum nigrum SCNU-F0002. The structures were elucidated on the interpretation of spectroscopic data. The absolute configuration of Compounds 2 and 3 were determined by comparison of their ECD spectra with the data of their analogue dihydroisocoumarins described in the literature. The absolute configuration of 4 was determined by single-crystal X-ray diffraction. All the compounds were screened for their antioxidant, antibacterial, anti-phytopathogenic fungi and cytotoxic activities. Using a DPPH radical-scavenging assay, Compounds 10–13 showed potent antioxidant activity with IC50 values of 13.6, 12.1, 18.1, and 11.7 μg/mL, respectively. In addition, Compounds 6 and 7 showed antibacterial effects against Bacillus subtilis (ATCC 6538), Escherichia coli (ATCC 8739), and Staphylococcus aureus (ATCC 6538), with MIC values in the range of 25–50 μg/mL.

Computational design, Synthesis of 4,6-dihydroxy-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity

Benzofuranone is a bicyclic ring where a benzene ring fused with a furanone. Computation chemistry plays a major role in the development of new lead molecules. Computational tools docking, virtual screening, ADMET prediction are utilised in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compounds IA, IB, ID, IE, IF, was found to be with potent activity.

Docking, Screening, Synthesis of 4-hydroxy-6-methyl-2-phenyl-1-benzofuran-3(2H)-one derivatives as new leads for anti-cancer activity

Auroneis a bicyclic ring where a benzene ring fused with a furanone. Docking is an efficient tool in the development of new lead molecules. Docking, virtual screening, ADMET prediction are prominent devices in the identification of new lead molecules. Synthetic chemistry plays a major in developing a series of potent anti-cancer agents. Benzofuranone was synthesized by reacting benzene diols, and triols with bromo phenyl acetonitrile yielded an imine derivative are converted to a ketone with treatment with hydrochloric acid then cyclised with sodium acetate. The compounds identity and purity were confirmed by spectral and analytical methods. Benzofuranone derivatives are screened antineoplastic activity was performed against human skin cancer cell line G361 at micro molecular concentrations. The compound IIIA was found to be with potent activity.

Enantioselective Acyl Migration Reactions of Furanyl Carbonates with Chiral DMAP Derivatives.

An efficient enantioselective acyl migration reaction of furanyl carbonates was developed to construct all-carbon quaternary stereogenic centers. In some cases, the reactions required only 0.05 mol % (minimum 500 ppm) of catalyst and showed a high turnover frequency value (TOF; 3640 h-1 ). Multigram-scale reactions (10 grams) also proceeded with high enantioselectivity (>99:1 e.r.) in quantitative yield. The catalyst was robust and easily recovered in 98 % yield. A wide range of functional groups were tolerated (15 examples, >98 % yield, up to >99:1 e.r.), and a variety of optically active 3,3'-disubstituted benzofuranone derivatives, which are useful intermediates for the synthesis of natural products and pharmaceuticals, were efficiently obtained. Control experiments on the catalyst structure (e.g., catalyst 1 a vs. 1 a' and 1 a'') and computational calculations revealed that both the catalytic activity and enantioselectivity should be enhanced by hydrogen bonding between catalyst and substrate. Moreover, this system was applied to the challenging γ-selective acyl migration reaction of furanyl carbonates with high γ-selectivity and high enantioselectivity (α:γ=10:90, 95:5 e.r.).

Evaluation of antioxidant and anti-proliferative efficacy of Nostoc muscorum NCCU-442

Abstract Natural sources have always been the primary sources of bioactive principles. Cyanobacteria with its wide spectrum of metabolites represents a favourable source of compounds having medicinal properties like antioxidant, anti-proliferative etc. In this study we tested different organic extracts [Diethyl ether (DE), Dichloromethane (DM), Ethyl acetate (EA) and Heptane (HE) extracts] of cyanobacterium Nostoc muscorum NCCU-442 for the same. Antioxidant activity was evaluated through DPPH and FRAP assay. Phenolic content was estimated using FCR reagent as phenolic compounds are the well-established antioxidants. MTT assay was used to estimate anti-proliferative activity against cervical cancer cell line, SiHa. DE extract was found to have the highest Phenolic content, i.e. 96.71 ± 2.41 mgGAE/g as well as most antioxidant effect in DPPH assay (IC50 =118 ± 0.34 µg/ml) and FRAP assay (EC1 =380.7 ± 2.43 µg/ml). The order of phenolic content of different extracts is: DE > EA> DM > HE. The order of antioxidant potential was same as the phenolic content. HE extract had the least antioxidant effect in the two assays (IC50 =686 ± 3.3 µg/ml and EC1 >10 mg/ml for DPPH and FRAP respectively). All the extracts showed anti-proliferative activity against the cancer cell line in the order: DE (IC50 = 70 ± 0.22 µg/ml) > HE (116.5 ± 0.53 µg/ml) > EA (205 ± 0.77 µg/ml) > DM (190 ± 0.45 µg/ml). During Gas Chromatography-Mass Spectrometry (GC-MS), bioactives like Benzofuranone derivatives, Myristoleic acid, Resorcinol, Citronellyl butyrates, hydroquinone, hexadecanoic acid, farnesol were identified in the organic extracts. Thus, our study indicated that Nostoc muscorum NCCU-442 has an inherent capacity as a potential source of therapeutic compounds.