Search Results (25)

Background/Objectives: Fraxetin (7,8-dihydroxy-6-methoxycoumarin), a coumarin constituent of Cortex Fraxini (Qinpi) used in traditional Chinese medicine, is metabolised mainly by UGT1A9, but its potential to inhibit UGT enzymes and cause herb–drug interactions (HDIs) is largely unstudied. Methods: Fraxetin and four related coumarins were screened against 11 recombinant human UGTs; isoforms inhibited ≥80% underwent full kinetic analysis with 4-methylumbelliferone as probe. Binding was examined by molecular docking on AlphaFold structures with PLIP, triplicate 100 ns molecular dynamics, and MM/GBSA and MM/PBSA free-energy calculations, and interaction risk by FDA 2020 in vitro–in vivo extrapolation (IVIVE). Results: Fraxetin alone inhibited both UGT1A1 and UGT1A9 by >80% and was characterised in detail, acting as a mainly competitive mixed-type inhibitor (UGT1A1 IC₅₀ 15.99 μM, K_i 8.32 μM; UGT1A9 IC₅₀ 8.44 μM, K_i 5.90 μM). A structure–activity comparison identified a dual-element pharmacophore comprising the C-6 methoxy group and the 7,8-dihydroxycoumarin aglycone. MM/GBSA favoured UGT1A9 over UGT1A1 (ΔΔG = −4.06 kcal/mol, p = 0.005), concordant with the kinetic ranking. IVIVE predicted a borderline systemic signal (R₁ > 1.02) but an intestinal R_1,gut approximately five- to seven-fold above the high-risk threshold of 11 after capping the luminal concentration at fraxetin aqueous solubility. Conclusions: This is the first characterisation of fraxetin as a moderate-potency inhibitor of UGT1A1 and UGT1A9 and points to a previously under-recognised herb–drug interaction risk concentrated in the intestinal lumen rather than systemically; the finding constitutes an interaction signal requiring clinical confirmation rather than an established risk. Full article

Kidney injury is a major clinical syndrome that can arise from nephrotoxins, ischemia–reperfusion, metabolic disease, infection, and immune dysregulation and can progress from acute kidney injury (AKI) to chronic kidney disease (CKD). Esculetin, a natural 6,7-dihydroxycoumarin derived from Cortex Fraxini, has antioxidant, anti-inflammatory, mitochondrial regulatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic activities. Preclinical studies report renoprotection in cisplatin-induced AKI, diabetes complicated by ischemia–reperfusion-induced AKI, and adenine-induced chronic renal injury, with changes in Nrf2/HO-1, NF-kappaB/MAPK, PINK1/Parkin-associated mitophagy, endoplasmic reticulum stress, regulated cell death, and fibrotic signaling. However, the evidence is based on a small number of heterogeneous cell and rodent studies, direct molecular targets remain uncertain, and no human studies have validated efficacy, dosing, or safety. Low oral bioavailability, rapid conjugative metabolism, limited long-term toxicology, and the absence of pharmacokinetic–pharmacodynamic relationships are major barriers to translation. This review critically synthesizes the renal evidence for esculetin and identifies the experimental, pharmaceutical, and clinical studies required to determine whether it can progress from a promising multi-target natural product to a renoprotective therapeutic candidate. Full article

Background: Esculetin, 6,7-dihydroxycoumarin, is a bioactive compound found in various herbal plants, and is known to have health-beneficial properties including anti-obesity effects. However, there is a lack of in vivo studies to clearly determine esculetin’s role in lipid metabolism. Objectives: In this study, we studied esculetin’s effect on lipid accumulation using Caenorhabditis elegans and its underlying mechanisms. Methods: C. elegans were treated with esculetin (100 or 200 μM) for 48 h, and their triglyceride and protein levels were measured. Additionally, behavioral patterns such as pharyngeal pumping rate, body bending rate, body sizes, and locomotive activity were analyzed. Genetic dependencies were examined by utilizing mutant worms and testing relative gene expressions. Results: C. elegans treated with esculetin displayed significantly reduced fat accumulation compared to the controls without effects on the pharyngeal pumping rate, body bending rate, or locomotive activity. Esculetin’s fat-lowering effect was dependent on DAF-2 (insulin/insulin-like growth factor-1 [IGF-1] receptor homolog), DAF-16 (Forkhead box protein O homolog), and AAK-2 (5′-adenosine monophosphate-activated protein kinase [AMPK] catalytic subunit α2) in the mutant experiments. Esculetin also significantly increased the relative expression of downstream targets of DAF-16 (hsp-16.2 and sod-3), AMPK-related genes (aak-1 and aak-2), a sirtuin gene, sir-2.1, and a lipolysis-related gene, atgl-1. Conclusions: These findings suggest that esculetin inhibited fat accumulation in C. elegans and this effect was dependent on the insulin/IGF-1 and 5′-adenosine monophosphate-activated protein kinase signaling pathways. Full article

In this study, adsorbents based on molecularly imprinted polymers (MIPs) in two solid-phase extraction application forms, pipette tip and magnetic extraction, were used for the selective extraction of coumarins. The pipette-tip solid-phase extraction reduced solvent volumes; the magnetic MIP extraction was simple and effective for phase separation. Parameters affecting extraction, such as the amount of adsorbent, type of washing solvent, volume of the elution solvent, and extraction times for magnetic extraction, were optimized. The MIP-based adsorbents displayed high selectivity and extraction efficiency, resulting in recoveries ranging from 70.3 to 102.0% (RSD % less than 5.5%) for five coumarins under study, 6,7-dihydroxycoumarin-6-β-D-glucoside, coumarin, 7-methoxycoumarin, 6-methylcoumarin, and dicoumarol. The extracts were analyzed by high-performance liquid chromatography with diode array (DAD) and fluorescence (FLD) detectors, reaching limits of quantification of 0.5 and 0.9 µg·mL⁻¹ for coumarin and dicoumarol detected by DAD and 0.001–0.012 µg·mL⁻¹ for the other prohibited simple coumarins when used as a fragrance (detected by FLD). The proposed method was validated and its applicability was shown for the analysis of cosmetic samples like shower gel and perfume. Full article

(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytostatic drugs (mitoxantrone, docetaxel, vemurafenib, epirubicin and cisplatin). (2) The viability, proliferation and cytotoxicity of daphnetin against four human malignant melanoma cell lines were evaluated. The interactions were assessed using isobolographic analysis for the combinations of daphnetin with each of the five cytostatic drugs. (3) Daphnetin showed anticancer activity against malignant melanoma, with IC₅₀ values ranging from 40.48 ± 10.90 µM to 183.97 ± 18.82 µM, depending on the cell line. The combination of daphnetin with either vemurafenib or epirubicin showed an antagonistic interaction. Moreover, additive interactions were observed for the combinations of daphnetin with cisplatin and docetaxel. The most desirable synergistic interactions for human melanoma metastatic cell lines were observed for the combination of daphnetin with mitoxantrone. (4) The obtained results suggest that daphnetin should not be combined with vemurafenib or epirubicin in the treatment of malignant melanoma due to the abolition of their anticancer effects. The combination of daphnetin with mitoxantrone is beneficial in the treatment of metastatic melanoma due to their synergistic interaction. Full article

Coumarins represent a broad class of compounds with pronounced pharmacological properties and therapeutic potential. The pursuit of the commercialization of these compounds requires the establishment of controlled and highly efficient degradation processes, such as advanced oxidation processes (AOPs). Application of this methodology necessitates a comprehensive understanding of the degradation mechanisms of these compounds. For this reason, possible reaction routes between HO^• and recently synthesized aminophenol 4,7-dihydroxycoumarin derivatives, as model systems, were examined using electron paramagnetic resonance (EPR) spectroscopy and a quantum mechanical approach (a QM-ORSA methodology) based on density functional theory (DFT). The EPR results indicated that all compounds had significantly reduced amounts of HO^• radicals present in the reaction system under physiological conditions. The kinetic DFT study showed that all investigated compounds reacted with HO^• via HAT/PCET and SPLET mechanisms. The estimated overall rate constants (k_overall) correlated with the EPR results satisfactorily. Unlike HO^• radicals, the newly formed radicals did not show (or showed negligible) activity towards biomolecule models representing biological targets. Inactivation of the formed radical species through the synergistic action of O₂/NO_x or the subsequent reaction with HO^• was thermodynamically favored. The ecotoxicity assessment of the starting compounds and oxidation products, formed in multistage reactions with O₂/NO_x and HO^•, indicated that the formed products showed lower acute and chronic toxicity effects on aquatic organisms than the starting compounds, which is a prerequisite for the application of AOPs procedures in the degradation of compounds. Full article

In this work, a novel portable and wireless intelligent electrochemical nanosensor was developed for the detection of 6,7-dihydroxycoumarin (6,7-DHC) using a modified screen-printed electrode (SPE). Black phosphorene (BP) nanosheets were prepared via exfoliation of black phosphorus nanoplates. The BP nanosheets were then mixed with nano-diamond (ND) to prepare ND@BP nanocomposites using the self-assembly method, achieving high environmental stability. The nanocomposite was characterized by SEM, TEM, Raman, XPS and XRD. The nanocomposite was used for the modification of SPE to improve its electrochemical performances. The nanosensor displayed a wide linear range of 0.01–450.0 μmol/L with a low detection limit of 0.003 μmol/L for 6,7-DHC analysis. The portable and wireless intelligent electrochemical nanosensor was applied to detect 6,7-DHC in real drug samples by the standard addition method with satisfactory recoveries, which extends the application of BP-based nanocomposite for electroanalysis. Full article

Polyphenols are valuable natural antioxidants present in our diet that likely mitigate aging effects, neurodegenerative conditions, and other diseases. However, because of their poor absorption in the gut and consequent low concentration in biological fluids (µM range), reservations about polyphenol antioxidant efficiency have been raised. In this review, it is shown that after scavenging superoxide radicals, coumarin, chalcone, and flavonoid polyphenols can reform themselves, becoming ready for additional cycles of scavenging, similar to the catalytic cycle in superoxide dismutase (SOD) action. The π-π interaction between one polyphenol ring and superoxide is associated with oxidation of the latter due to transfer of its unpaired electron to a polyphenolic aromatic ring, and consequent formation of a molecule of O₂ (one product of SOD action). Mechanistically, it is very difficult to establish if this π-π interaction proceeds before or after the most common mode of scavenging superoxide, e.g., abstraction of an aromatic polyphenol H(hydroxyl), which then is used to form H₂O₂ (the other molecule produced by SOD action). At the end of this cycle of superoxide scavenging, 4-methyl-7,8-di-hydroxy-coumarin and the flavonoid galangin reform themselves. An alternative mechanistic pathway by galangin forms the η-(H₂O₂)-galangin-η-O₂ complex that includes additional H₂O₂ and O₂ molecules. Another mode of action is seen with the chalcone butein, in which the polyphenol system incorporates a molecule of O₂, e.g., a η-O₂-butein complex is formed, ready for additional scavenging. Of the several families of polyphenols analyzed in this review, only butein was able to circumvent an initial π-π interaction, directing the superoxide towards H(hydroxyl) in position 4, e.g., acting as a typical polyphenol scavenger of superoxide. This fact did not impede an additional superoxide to later react with the aromatic ring in π-π fashion. It is concluded that by mimicking SOD enzyme action, the low concentration of polyphenols in biological fluids is not a limiting factor for effective scavenging of superoxide. Full article

Skin aging is a progressive biological process of the human body, and it is not only time-dependent. Differently substituted 3-phenylcoumarins proved to efficiently inhibit tyrosinase. In the current work, new substitution patterns have been explored, and the biological studies were extended to other important enzymes involved in the processes of skin aging, as elastase, collagenase and hyaluronidase. From the studied series, five compounds presented inhibitory activity against tyrosinase, one compound against elastase, eight compounds against collagenase and two compounds against hyaluronidase, being five compounds dual inhibitors. The 3-(4′-Bromophenyl)-5,7-dihydroxycoumarin (1) and 3-(3′-bromophenyl)-5,7-dihydroxycoumarin (2) presented the best profiles against tyrosinase (IC₅₀ = 1.05 µM and 7.03 µM) and collagenase (IC₅₀ = 123.4 µM and 110.4 µM); the 3-(4′-bromophenyl)-6,7-dihydroxycoumarin (4) presented a good inhibition against tyrosinase and hyaluronidase; the 3-(3′-bromophenyl)-6,7-dihydroxycoumarin (5) showed an effective tyrosinase and elastase inhibition; and 6,7-dihydroxy-3-(3′-hydroxyphenyl)coumarin (11) presented a dual profile inhibition against collagenase and hyaluronidase. Furthermore, considering the overall activities tested, compounds 1 and 2 proved to be the most promising anti-aging compounds. These compounds also showed to have a photo-protective effect, without being cytotoxic to human skin keratinocyte cells. To predict the binding site with the target enzymes, computational studies were also carried out. Full article

To expand the range of daphnetin-based inhibitors/activators used for targeting G protein-coupled receptors (GPCRs) in disease treatment, twenty-five coumarin derivatives 1–25, including 7,8-dihydroxycoumarin and 7-hydroxycoumarin derivatives with various substitution patterns/groups at C3-/4- positions, were synthesized via mild Pechmann condensation and hydroxyl modification. The structures were characterized by ¹H NMR, ¹³C NMR and ESI-MS. Their inhibition or activation activities relative to GPCRs were evaluated by double-antibody sandwich ELISA (DAS–ELISA) in vitro. The results showed that most of the coumarin derivatives possessed a moderate GPCR activation or inhibitory potency. Among them, derivatives 14, 17, 18, and 21 showed a remarkable GPCR activation potency, with EC₅₀ values of 0.03, 0.03, 0.03, and 0.02 nM, respectively. Meanwhile, derivatives 4, 7, and 23 had significant GPCR inhibitory potencies against GPCRs with IC₅₀ values of 0.15, 0.02, and 0.76 nM, respectively. Notably, the acylation of hydroxyl groups at the C-7 and C-8 positions of 7,8-dihydroxycoumarin skeleton or the etherification of the hydroxyl group at the C-7 position of the 7-hydroxycoumarin skeleton could successfully change GPCRs activators into inhibitors. This work demonstrated a simple and efficient approach to developing coumarin derivatives as remarkable GPCRs activators and inhibitors via molecular diversity-based synthesis. Full article

The fruits of Lycium barbarum are rich in flavonoids, which may contribute to the health-promoting function of Lycium barbarum. However, the composition of flavonoids in the fruits of Lycium barbarum (LBFs) has received little attention. Thus, the goal of this work was to identify more kinds of flavonoids from fruits of Lycium barbarum by liquid chromatography–mass spectrometry. The potential antioxidant and anti-inflammatory activities of LBFs in vitro were also investigated. Thirteen flavonoid compounds were identified in LBFs, of which daphnetin, 6,7-dihydroxycoumarin, astragalin, taxifolin, eriodictyol, naringenin, and chrysoeriol were identified for the first time in the fruits of Lycium barbarum, which greatly enriched the variety of flavonoids in the fruits of Lycium barbarum. LBFs showed a similar superior antioxidant activity to vitamin C. Furthermore, LBFs exhibited an anti-inflammatory activity by suppressing the production of nitric oxide and pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1β, and interleukin-6, in lipopolysaccharide-treated RAW264.7 macrophage cells. This study demonstrated the potential development of LBFs as functional foods. Full article

Coumarin derivatives have proven beneficial biological activities, but the mechanism of their radical scavenging potency is not fully understood. In this study, the antiradical capacity of two newly synthesized 4,7-dihydroxycoumarin derivatives: (E)-3-(1-((3-hydroxy-4-methoxyphenyl)amino)-ethylidene)-2,4-dioxochroman-7-yl acetate (A-3OH) and (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A-4OH) towards HO^• were examined by Electron Paramagnetic Resonance (EPR) Spectroscopy and Density Functional Theory (DFT). The compounds were fully characterized by the elemental microanalysis, IR, and NMR spectroscopies. The effect of pH on the acid–base equilibria is separately discussed and the predominant species at the physiological pH were determined. Several common mechanisms (Hydrogen Atom Transfer (HAT), Single-Electron Transfer followed by Proton Transfer (SET-PT), Sequential Proton Loss followed by Electron Transfer (SPLET), Radical Adduct Formation (RAF), and Intramolecular Hydrogen Atom Abstraction (iHAA)) of radical scavenging were investigated based on thermodynamic and kinetic parameters. EPR results indicated that both compounds significantly reduce the amount of present HO^•. The results of the kinetic DFT study demonstrated that both compounds predominantly exhibit antiradical capacity through HAT and SPLET mechanisms. The estimated overall rate constants (k_overall) proved that A-4OH shows better antioxidant capacity than A-3OH which is well-correlated with the results obtained by EPR measurement. Full article

A set of 3-ethynylaryl coumarin dyes with mono, bithiophenes and the fused variant, thieno [3,2-b] thiophene, as well as an alkylated benzotriazole unit were prepared and tested for dye-sensitized solar cells (DSSCs). For comparison purposes, the variation of the substitution pattern at the coumarin unit was analyzed with the natural product 6,7-dihydroxycoumarin (Esculetin) as well as 5,7-dihydroxycomarin in the case of the bithiophene dye. Crucial steps for extension of the conjugated system involved Sonogashira reaction yielding highly fluorescent molecules. Spectroscopic characterization showed that the extension of conjugation via the alkynyl bridge resulted in a strong red-shift of absorption and emission spectra (in solution) of approximately 73–79 nm and 52–89 nm, respectively, relative to 6,7-dimethoxy-4-methylcoumarin (λ_abs = 341 nm and λ_em = 410 nm). Theoretical density functional theory (DFT) calculations show that the Lowest Unoccupied Molecular Orbital (LUMO) is mostly centered in the cyanoacrylic anchor unit, corroborating the high intramolecular charge transfer (ICT) character of the electronic transition. Photovoltaic performance evaluation reveals that the thieno [3,2-b] thiophene unit present in dye 8 leads to the best sensitizer of the set, with a conversion efficiency (η = 2.00%), best V_OC (367 mV) and second best J_sc (9.28 mA·cm⁻²), surpassed only by dye 9b (J_sc = 10.19 mA·cm⁻²). This high photocurrent value can be attributed to increased donor ability of the 5,7-dimethoxy unit when compared to the 6,7 equivalent (9b). Full article

The phenolics profile, free amino acids composition, and antioxidant potential of rosemary infusions were studied. Forty-four compounds belonging to nine different groups (hydroxybenzoic acids, hydroxycinnamic acids, flavan-3-ols, flavanones, flavones, phenolic diterpenes, hydroxybenzaldehydes, coumarins, and pyranochromanones) were identified by UHPLC-ESI-Q-TOF-MS. Of these, seven were firstly described in rosemary infusions: a rosmanol derivative, two dihydroxycoumarin hexosides, a hydroxybenzaldehyde, a dihydroxybenzoic acid hexoside, coumaric acid hexoside, and isocalolongic acid. The free amino acid profile of the beverages was also reported by the first time with seven amino acids found (asparagine, threonine, alanine, tyrosine, phenylalanine, isoleucine, and proline). Furthermore, DPPH^• scavenging ability, Ferric Reducing Antioxidant Power and Oxygen Radical Absorbance Capacity, as well as total phenolics and flavonoids contents, were assessed. Overall, rosemary infusions showed to be a very good source of antioxidants. A 200 mL cup of this infusion contributes to the ingestion of ~30 mg of phenolic compounds and about 0.5–1.1 μg of free amino acids. This type of beverages may present a positive impact on the maintenance of the body antioxidant status and contribute to the prevention of oxidative stress related diseases. Full article

Coumarins are well known secondary metabolites widely found in various plants. However, the degradation of these compounds in the environment has not been studied in detail, and, especially, the initial stages of the catabolic pathways of coumarins are not fully understood. A soil isolate Pseudomonas mandelii 7HK4 is able to degrade 7-hydroxycoumarin (umbelliferone) via the formation of 3-(2,4-dihydroxyphenyl)propionic acid, but the enzymes catalyzing the α-pyrone ring transformations have not been characterized. To elucidate an upper pathway of the catabolism of 7-hydroxycoumarin, 7-hydroxycoumarin-inducible genes hcdD, hcdE, hcdF, and hcdG were identified by RT-qPCR analysis. The DNA fragment encoding a putative alcohol dehydrogenase HcdE was cloned, and the recombinant protein catalyzed the NADPH-dependent reduction of 7-hydroxycoumarin both in vivo and in vitro. The reaction product was isolated and characterized as a 7-hydroxy-3,4-dihydrocoumarin based on HPLC-MS and NMR analyses. In addition, the HcdE was active towards 6,7-dihydroxycoumarin, 6-hydroxycoumarin, 6-methylcoumarin and coumarin. Thus, in contrast to the well-known fact that the ene-reductases usually participate in the reduction of the double bond, an alcohol dehydrogenase catalyzing such reaction has been identified, and, for P. mandelii 7HK4, 7-hydroxycoumarin degradation via a 7-hydroxy-3,4-dihydrocoumarin pathway has been proposed. Full article