Flavone Derivatives Research Articles

Synthesis of Flavone Derivatives through Versatile Palladium-Catalyzed Cross-Coupling Reactions of Tosyloxy- and Mesyloxyflavones

Tosyloxy- and mesyloxyflavones derived from abundant and biologically important hydroxyflavones were used to synthesize a series of functionalized flavones through versatile palladium-catalyzed cross-coupling reactions. A Pd(OAc)2/2-[2-(dicyclohexylphosphino)phenyl]-1-methyl-1H-indole system effectively catalyzed the reactions of a broad range of tosyloxy- and mesyloxyflavones as electrophilic coupling partners with various nucleophiles to give the corresponding products in good to excellent yields. Catalyst loadings of as little as 0.1 mol% Pd were successfully used. Importantly, we demonstrated that this protocol provided a significantly improved efficiency in the synthesis of a potential chromen-4-one-based analogue of a potent inhibitor of DNA-dependent protein kinase.

Synthesis and Heme Polymerization Inhibitory Activity (HPIA) Assay of Chalcone, Flavone and Flavanone Derivatives

Chalcone, flavone, and flavanone had been synthesized as candidate of the antimalarial compounds. The chalcone 1was synthesised from 2,4-dihydroxyacetophenone and 4-metoxybenzaldehyde as starting materials using base catalyst KOH via Claisen-Schmidt Condensation. The synthesis flavone 2was carried out by cyclization of chalcone 1using I2 in DMSO, while the flavanone 3was produced by cyclization of chalcone 1using NaOAc as a base catalyst. An in vitro antimalarial activity of the compound 1, 2and 3have been evaluated with the chloroquine diphosphate as a positive control in various concentration, and this assay was carried out according to the Basilico method. The IC50value of compound 1, 2, 3and a positive control were 0.25; 0.62; 1.33 and 0.35 mM, respectively. The result showed that chalcone1with the lowestIC50value is a potential candidate as an antimalarial agent.

Intramolecular Excited-State Proton Transfer in Biologically Active Flavones: A Combined Experimental and Theoretical Study

The absorption and fluorescence characteristics of two biologically active flavone derivatives 6-hydroxy-7,3’,4’,5’-tetramethoxyflavone (6HTMF) and 7-hydroxy-6,3’,4’,5’-tetramethoxyflavone (7HTMF) were studied as a function of acidity (pH/H0) of the solution. Dissociation constants were determined for ground and first excited singlet states and the results were compared with those obtained from Forster-Weller calculations. The acidity constants for these two compounds (6HTMF and 7HTMF) obtained from fluorimetric titrations are in poor agreement with those obtained from Forster-Weller data but are in good agreement with ground state pKa values indicated the deactivation of excited state (S1) before the prototropic equilibrium is complete. The broad band emission of both the flavones in acidic aqueous solution suggests their use as tuneable dye lasers. 6-Hydroxy-7,3’,4’,5’-tetramethoxyflavone undergoes adiabatic photo-dissociation in the singlet excited state indicating the formation of an exciplex or a photo-tautomer. The stability of photo-tautomer was confirmed by calculated value of enthalpy of formation using AM1 method.

DESIGN, SYNTHESIS AND MOLECULAR MECHANISM OF FEW NEURAMINIDASE INHIBITORS IN TREATMENT OF H1N1 BY NMR TECHNIQUES

Considering the issue of resistance to anti-influenza drugs, there is a need for discovery of new antiviral drugs. In view of this, flavones and their synthetic precursors i.e. chalcones were designed as inhibitors of influenza virus - H1N1 neuraminidase enzyme using structure-based drug design. Based on the best docking scores, some chalcone and flavone derivatives were synthesized and characterized by IR and proton NMR. Few of them were selected for 31P NMR studies, in order to probe the molecular mechanism of their antiviral action. Reasonably good correlation between docking scores and 31P NMR results were observed. As antiviral drugs are known to show membrane stabilizing effect on host cell, 31P NMR data for methoxy chalcone showed stabilization effect on model membrane pointing towards good antiviral activity which remained unaffected even after its cyclization to flavone. These derivatives can be explored further to provide a future therapeutic option for the treatment and prophylaxis of H1N1 viral infections.

SYNTHESIS, BIOLOGICAL EVALUATION, AND DOCKING STUDY OF NOVEL 2-PHENYL-1- BENZOPYRAN-4-ONE DERIVATIVES - AS A POTENT CYCLOOXYGENASE-2 INHIBITOR

Objective: The inflammation and oxidative stress were related together in the generation of reactive oxygen species, which is responsible for the enhancement of inflammation associated with various chronic diseases.
 Methods: The aim of this study is to synthezise and characterizes the flavones (2-phenyl-1-benzopyran-4-one) derivatives and analyzed by their docking hypothetical data as an effective anti-inflammatory mediator against cyclooxygenase-2 (COX-2) enzyme. Further, the evaluation of various in vitro antioxidant and anti-inflammatory studies was carried out.
 Results: The 10 compounds were synthesized and characterized by ultraviolet, infrared, nuclear magnetic resonance, and mass spectroscopic techniques. The docking data results of these 10 flavones derivatives against COX-2 enzymes (Protein Data Bank ID: 3LN1) showed the binding energy ranging between −5.53 kcal/mol and −7.02 kcal/mol when compared with that of the standard diclofenac (−6.34 kcal/mol). The in vitro studies suggest that the lipophilic character of the side chain donor, along with the hydroxyl substituted flavones found to have significant half maximal inhibitory concentration values.
 Conclusion: Based on these in silico and in vitro evaluation results, these synthesized compounds could act as a promising inhibitor to target the COX- 2 enzyme. Hence, those compounds were effective in the management of chronic diseases by exhibits free radical scavenging and anti-inflammatory property.

A review on flavones targeting serine/threonine protein kinases for potential anticancer drugs.

Protein kinases have been important targets for antitumor targets due to their key roles in regulating multiple cell signaling pathways. Numerous compounds containing flavonoid scaffold as an indispensable anchor have been found to be potent inhibitors of protein kinases. Some of these flavonoids have been in clinical research as protein kinases inhibitors. Thus, the present review mainly focuses on the structural requirement for anticancer potential of flavone derivatives targeting several key serine/threonine protein kinases. This information may provide an opportunity to scientists of medicinal chemistry to design multi-functional flavone derivatives for the treatment of cancer.

Biocatalytic oxidation of flavone analogues mediated by general biocatalysts: horseradish peroxidase and laccase.

Horseradish peroxidase (HRP) and laccase are well known oxidases, which have been widely applied for the biosynthesis of organic compounds. In the present work, flavone analogues as an important type of bioactive natural product could be oxidized by HRP or laccase, which afforded dimeric and oxidative flavones. All of the flavone analogues usually possessing phenolic groups could be transformed using HRP. However, only flavonols, isoflavones and chalcones with phenolic groups and dihydroxylflavones were effective substrates of laccase. The radical reaction mechanism with the B-ring of flavone analogues as the radical reaction trigger was proposed for the oxidation of flavones. In silico molecular docking analyses for assaying the interaction between flavone analogues and oxidases indicated that the phenolic groups at the B rings of flavones docked into the HEME active pocket of HRP well. Kinetic behaviors of the oxidation for various flavone analogues mediated by HRP or laccase displayed Hill and substrate inhibition kinetic models. Therefore, in the present work, the oxidation of various flavone analogues mediated by HRP or laccase has been successfully characterized, which would be helpful for the preparation of flavone derivatives.

Synthesis of ArSe-Substituted Flavone Derivatives Using Se Powder

Synthesis of ArSe-Substituted Flavone Derivatives Using Se Powder

New Alkoxy Flavone Derivatives Targeting Caspases: Synthesis and Antitumor Activity Evaluation.

The antitumor activity of natural flavonoids has been exhaustively reported. Previously it has been demonstrated that prenylation of flavonoids allows the discovery of new compounds with improved antitumor activity through the activation of caspase-7 activity. The synthesis of twenty-five flavonoids (4–28) with one or more alkyl side chains was carried out. The synthetic approach was based on the reaction with alkyl halide in alkaline medium by microwave (MW) irradiation. The in vitro cell growth inhibitory activity of synthesized compounds was investigated in three human tumor cell lines. Among the tested compounds, derivatives 6, 7, 9, 11, 13, 15, 17, and 18 revealed potent growth inhibitory activity (GI50 < 10 μM), being the growth inhibitory effect of compound 13 related with a pronounced caspase-7 activation on MCF-7 breast cancer cells and yeasts expressing human caspase-7. A quantitative structure-activity relationship (QSAR) model predicted that hydrophilicity, pattern of ring substitution/shape, and presence of partial negative charged atoms were the descriptors implied in the growth inhibitory effect of synthesized compounds. Docking studies on procaspase-7 allowed predicting the binding of compound 13 to the allosteric site of procaspase-7.

Inhibitory Effect of Synthetic Flavone Derivatives on Pan-Aurora Kinases: Induction of G2/M Cell-Cycle Arrest and Apoptosis in HCT116 Human Colon Cancer Cells.

Members of the aurora kinase family are Ser/Thr kinases involved in regulating mitosis. Multiple promising clinical trials to target aurora kinases are in development. To discover flavones showing growth inhibitory effects on cancer cells, 36 flavone derivatives were prepared, and their cytotoxicity was measured using a long-term clonogenic survival assay. Their half-maximal growth inhibitory effects against HCT116 human colon cancer cells were observed at the sub-micromolar level. Pharmacophores were derived based on three-dimensional quantitative structure–activity calculations. Because plant-derived flavones inhibit aurora kinase B, we selected 5-methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one (derivative 31), which showed the best half-maximal cell growth inhibitory effect, and tested whether it can inhibit aurora kinases in HCT116 colon cancer cells. We found that derivative 31 inhibited the phosphorylation of aurora kinases A, aurora kinases B and aurora kinases C, suggesting that derivative 31 is a potential pan-aurora kinase inhibitor. The results of our analysis of the binding modes between derivative 31 and aurora A and aurora B kinases using in-silico docking were consistent with the pharmacophores proposed in this study.

α-Glucosidase inhibition activity and in silico study of 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one, a synthetic derivative of flavone.

A synthetic flavone derivative 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one (BDC) was synthesized by the one pot reaction method and assessed for α-glucosidase inhibitory activity. The BDC demonstrated dose dependent inhibition of α-glucosidase activity. A maximum inhibition (99.3 ± 0.26%) of α-glucosidase was observed at 27.6 µM. The maximum α-glucosidase inhibitory activity depicted by BDC 27.6 µM concentration was 22.4 fold over the maximum inhibition observed with acarbose (97.72 ± 0.59% at 669.57 µM), a standard commercial anti-diabetic drug. In contrast to acarbose that depicted competitive type inhibition, kinetic studies of α-glucosidase inhibition by BDC demonstrated non-competitive inhibition with Km of 0.71 mM-1 and a Vmax of 0.028 mmol/min. In silico studies suggest allosteric interaction of BDC with α-glucosidase at a minimum binding energy (ΔG) of -8.64 kcal/mol and Ki of 465.3 nM, whereas, acarbose interacted at the active site of α-glucosidase with ΔG of -9.23 kcal/mol and Ki of 172 nM. Thus BDC significantly inhibited α-glucosidase in comparison to acarbose. Moreover, BDC has been endorsed for drug likeness by evaluating it as per Lipinski rule of five. Thus, BDC can be a lead compound for the management of type-2 diabetes mellitus.

Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2

During cancer chemotherapy, certain cancers may become cross-resistant to structurally diverse antineoplastic agents. This so-called multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transport proteins. These membrane-bound efflux pumps export a broad range of structurally diverse endo- and xenobiotics, including chemically unrelated anticancer agents. This translocation of drugs from the inside to the outside of cancer cells is mediated at the expense of ATP. In the last 40 years, three ABC transporters – ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) – have mainly been attributed to the occurrence of MDR in cancer cells. One of the strategies to overcome MDR is to inhibit the efflux transporter function by small-molecule inhibitors. In this work, we investigated new chalcone- and flavone-based compounds for selective as well as broad-spectrum inhibition of the stated transport proteins. These include substituted chalcones with variations at rings A and B, and flavones with acetamido linker at position 3. The synthesized molecules were evaluated for their inhibitory potential against ABCB1, ABCC1, and ABCG2 in calcein AM and pheophorbide A assays. In further investigations with the most promising candidates from each class, we proved that ABCB1- and ABCG2-mediated MDR could be reversed by the compounds. Moreover, their intrinsic toxicity was found to be negligible in most cases. Altogether, our findings contribute to the understanding of ABC transport proteins and reveal new compounds for ongoing evaluation in the field of ABC transporter-mediated MDR.

Effect of in vitro gastrointestinal digestion on the total phenolic contents and antioxidant activity of wild Mediterranean edible plant extracts

The recent interest in wild edible plants is associated with their health benefits, which are mainly due to their richness in antioxidant compounds, particularly phenolics. Nevertheless, some of these compounds are metabolized after ingestion, being transformed into metabolites frequently with lower antioxidant activity. The aim of the present study was to evaluate the influence of the digestive process on the total phenolic contents and antioxidant activity of extracts from four wild edible plants used in the Mediterranean diet (Beta maritima L., Plantago major L., Oxalis pes-caprae L. and Scolymus hispanicus L.). HPLC-DAD analysis revealed that S. hispanicus is characterized by the presence of caffeoylquinic acids, dicaffeoylquinic acids and flavonol derivatives, P. major by high amounts of verbascoside, B. maritima possesses 2,4-dihydroxybenzoic acid, 5-O-caffeoylquinic acid, quercetin derivatives and kaempferol-3-O-rutinoside, and O. pes-caprae extract contains hydroxycinnamic acids and flavone derivatives. Total phenolic contents were determined by Folin–Ciocalteu assay, and antioxidant activity by the ABTS, DPPH, ORAC and FRAP assays. Phenolic contents of P. major and S. hispanicus extracts were not affected by digestion, but they significantly decreased in B. maritima after both phases of digestion process and in O. pes-caprae after the gastric phase. The antioxidant activity results varied with the extract and the method used to evaluate the activity. Results showed that P. major extract has the highest total phenolic contents and antioxidant activity, with considerable values even after digestion, reinforcing the health benefits of this species.

Design, synthesis and biological evaluation of novel flavone Mannich base derivatives as potential antibacterial agents.

A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids. After that, four bacteria were used to test antibacterial experiments of these compounds; compound 5g (MIC = 0.5, 0.125mg/L) showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin (MIC = 2, 0.25mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MIC = 1, 0.5, 2, 0.05mg/L) against four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC50 values (0.25-16mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial antibacterial agents.

3-Hydroxy-2-(4-methylphenyl)-4H-chromen-4-one

Our work in the area of carbon-monoxide-releasing molecules led to the synthesis and crystallization of new flavone derivatives as intermediates. Herein we report the first crystal structure of the title compound, C16H12O3, a hydroxy-substituted flavone where the 2-phenyl group has been replaced by a p-tolyl group. The introduction of the 3-hydroxy group allows the formation of intermolecular O—H...O=C hydrogen bonds, used to build centrosymmetric R 2 2(10) ring motifs in the crystal.

Characterization of New Polyphenolic Glycosidic Constituents and Evaluation of Cytotoxicity on a Macrophage Cell Line and Allelopathic Activities of Oryza sativa.

Four new constituents, as 5, 7-dihydroxy-4′-methoxyflavonol-3-O-β-d-arabinopyranosyl-(2′′→1′′′)-O-β-d-arabinopyrnosyl-2′′′-O-3′′′′, 7′′′′-dimethylnonan-1′′′′-oate (1), 5-hydroxy-7, 4′-dimethoxyflavone-5-O-α-d-arabinopyranosyl-(2"→1′′′)-O-α-d-arabinopyranosyl-2′′′-O-3′′′′, 7′′′′-dimethylnonan-1′′′′-oate (2), 5-hydroxy-7, 4′-dimethoxyflavone-5-O-β-d-arabinofuranosyl-(2"→1′′′)-O-β-d-arabinopyranosyl-2′′′-O-lanost-5-ene (3) and 4′,4′′-diferuloxy feruloyl-O-α-d-arabinopyranosyl-(2a→1b)-O-α-d-arabinopyranosyl-(2b→1c)-O-α-d-arabinopyranosyl-(2c→1d)-O-α-d-arabinopyranosyl-(2d→1e)-O-α-d-arabinopyranosyl-2e-3′′′, 7′′′-dimethylnonan-1′′′-oate (4), along with three known compounds (5–7) were isolated from Oryza sativa leaves and straw. The structures of new and known compounds were elucidated by 1D (1H and 13C NMR) and 2D NMR spectral methods, viz: COSY, HMBC, and HSQC aided by mass techniques and IR spectroscopy. The cytotoxicity of these constituents was assessed by using (RAW 264.7) mouse macrophage cell line, and allelopathic effects of compounds (1–7) on the germination and seedling growth characteristics such as seedling length and root length of barnyardgrass (Echinochloa oryzicola) were evaluated. Significant inhibitory activity was exhibited by compounds comprising flavone derivatives such as (1–3) on all of seed germination characteristics. The allelopathic effect of flavone derivatives were more pronounced on seedling length and root length than the germination characteristics. The higher concentration of flavone derivatives showed stronger inhibitory effects, whereas the lower concentrations showed stimulatory effects in some cases.

Synthesis and Antiproliferative Activity of Imidazole and Triazole Derivatives of Flavonoids

Flavones can play a potential role in estrogen dependent breast cancer due to greater reactivity of imidazole and triazole heterocycles which have been investigated in this work. We emphasized on synthesis of flavones derivatives with imidazole (2a, 2b, 2c) and triazole (3a, 3b, 3c) nucleus as a fundamental hetero-aromatic system with modifications, which have been confirmed by TLC, IR, NMR and mass spectrometry data. The synthesized compound were studied as non-steroidal aromatase inhibitors and evaluated for in vitro anti-breast cancer activity against MCF-7 cell line through SRB assay. The triazole derivative 3a with nitro substitution (H-bond accepting group) was found to be more active in comparison to standard drug letrozole.

Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds.

The serum and glucocorticoid-regulated kinase (SGK) family has been implicated in the regulation of many cellular processes downstream of the PI3K pathway. It plays a crucial role in PI3K-mediated tumorigenesis, making it a potential therapeutic target for cancer. SGK family consists of three isoforms (SGK1, SGK2, and SGK3), which have high sequence homology in the kinase domain and similar substrate specificity with the AKT family. In order to identify novel compounds capable of inhibiting SGK3 activity, a high-throughput screening campaign against 50,400 small molecules was conducted using a fluorescence-based kinase assay that has a Z' factor above 0.5. It identified 15 hits (including nitrogen-containing aromatic, flavone, hydrazone, and naphthalene derivatives) with IC50 values in the low micromolar to sub-micromolar range. Four compounds with a similar scaffold (i.e., a hydrazone core) were selected for structural modification and 18 derivatives were synthesized. Molecular modeling was then used to investigate the structure-activity relationship (SAR) and potential protein-ligand interactions. As a result, a series of SGK inhibitors that are active against both SGK1 and SGK3 were developed and important functional groups that control their inhibitory activity identified.

A Comparative Study between Co‐ and CoFe2O4‐NPs Catalytic Activities in Synthesis of Flavone Derivatives; Study of Their Interactions with Estrogen Receptor by Molecular Docking

AbstractFlavonols are polyphenolic compounds with diverse pharmacological and biological activities. In this work, a general method for large‐scale synthesis of these biologically important compounds, using available substrates, is reported. The reaction was occurred via Michael‐dehydrogenative reaction using green, inexpensive and highly efficient heterogeneous cobalt catalysts without any ligands and/or additives, the activity of CoFe2O4 and Co‐NPs was studied and compared. These procedures have advantages such as lack of hazardous oxidants, simplicity of work‐up, eco‐friendly of reaction medium, mild reaction conditions and high yield of products. In addition, the binding modes of synthesized compounds to estrogen receptor (ER) was studied by molecular docking and good results was obtained.

Studies on the interaction of a synthetic nitro-flavone derivative with DNA: A multi-spectroscopic and molecular docking approach

Interaction of a ligand with DNA is often the basis of drug action of many molecules. Flavones are important in this regard as their structural features confer them the ability to bind to DNA. 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO) is an important biologically active synthetic flavone derivative. We are therefore interested in studying its interaction with DNA. Absorption spectroscopy studies included standard and reverse titration, effect of ionic strength on titration, determination of stoichiometry of binding and thermal denaturation. Spectrofluorimetry techniques included fluorimetric titration, quenching studies and fluorescence displacement assay. Assessment of relative viscosity and estimation of thermodynamic parameters from CD spectral studies were also undertaken. Furthermore, molecular docking analyses were also done with different short DNA sequences. The fluorescent flavone 4NCO reversibly interacted with DNA through partial intercalation as well as minor-groove binding. The binding constant and the number of binding sites were of the order 104 M−1 and 1 respectively. The binding stoichiometry with DNA was found to be 1:1. The nature of the interaction of 4NCO with DNA was hydrophobic in nature and the process of binding was spontaneous, endothermic and entropy-driven. The flavone also showed a preference for binding to GC rich sequences. The study presents a profile for structural and thermodynamic parameters, for the binding of 4NCO with DNA. DNA is an important target for ligands that are effective against cell proliferative disorders. In this regard, the molecule 4NCO is important since it can exert its biological activity through its DNA binding ability and can be a potential drug candidate.