DNA and hemoglobin binding activities: Investigation of coumarin-thiosemicarbazone hybrids.

Coumarin and coumarin-thiosemicarbazone hybrids were synthesized and characterized by various techniques such as FT-IR, 1H NMR, 13C NMR, MALDI-TOF-MS spectroscopy, and single crystal X-Ray diffractometer (XRD). The photochemical and photophysical properties of the compounds, such as solvatochromism, solubility, and chemical reactivity, were analyzed using UV-vis spectroscopy in different solvents. Due to the potential biological activities of the synthesized compounds, their binding affinity and mechanisms with calf thymus DNA (ct-DNA) and bovine hemoglobin (BHb) were determined using several useful spectrophotometric and theoretical approaches such as UV-vis absorption and fluorescence spectroscopy, molecular docking, and density functional theory (DFT). The experimental results showed that the compounds exhibited strong binding interactions with DNA and BHb. Additionally, the compounds demonstrated predominantly binding modes, such as intercalation and groove binding with DNA and π-π stacking interactions with BHb.To better understand the thermodynamics of these interactions, quenching constants, binding constants, and Gibbs free energy changes (ΔG°) were calculated. Molecular docking and DFT results supported the experimental data regarding the binding affinity and mechanisms of the compounds to DNA and BHb. Overall, this comprehensive study on coumarin and coumarin-thiosemicarbazone hybrids provides valuable insights into their interaction mechanisms with critical biomolecules, highlighting their potential in therapeutic applications as multifunctional agents.

[Synthesis of Coumarin-oligonucleiotide Conjugates for Application in DNA-encoded Libraries].

Oligonucleotides, including DNA and RNA, can be functionalized by chemical modification based on synthetic organic chemistry. For example, ligand-oligonucleotide conjugates have a wide variety of applications. Conjugates of functional ligands and oligonucleotides have attracted attention in recent years as a drug delivery system (DDS) for improving the efficacy of oligonucleotide therapeutics. In addition, oligonucleotide conjugates with drug candidate compounds as ligands have been applied to drug screening using DNA-encoded libraries (DELs). Against this background, we have focused on the development of practical synthetic methods for ligand-oligonucleotide conjugates. Recently, we have developed a new synthetic method to construct oligonucleotides conjugated with coumarins and dipeptides, which are expected to have bioactivity, for application to DDS research of oligonucleotide therapeutics and drug discovery research using DEL. In this review, we will discuss the details, including how to construct a coumarin scaffold on oligonucleotides based on Knoevenagel condensation.

Estimation of Electric Dipole Moment by Solvatochromism, Computational Method, and Study of the Effect of Solvents by Preferential Solvation of 6 - Methoxy-4-(4-Nitro-Phenoxy Methyl)-Chromen-2-One (6mnpm).

At room temperature, the absorption and fluorescence properties of coumarin 6-Methoxy-4-(4-nitro-phenoxy methyl)-chromen-2-one (6MNPM) are investigated in pure organic solvents and a combination of acetonitrile (ACN) and tetrahydrofuran (THF). The pure solvents' influence on spectral characteristics is examined by applying theories such as Kamlet and Catalan's multiple linear regression techniques, Reichardt's microscopic solvent polarity parameter, and the Lippert-Mataga polarity function. The significant role of solute-solvent interactions in pure solvents, particularly dielectric interaction and hydrogen bonding. However, hydrogen bonding interactions dominate the contribution of dielectric interactions. The electric dipole moments of both the ground as well as excited states had been calculated using the Solvatochromic method. The value of the excited state electric dipole moment and the redshifts of the emission spectra show that the emitting singlet state has an intramolecular charge transfer (ICT) character. From Catalan's linear regression, we found that di-polarity has a much smaller influence than polarizability. By solvation study, we conclude that Tetrahydrofuran solvent is preferred over Acetonitrile.

Coumarin: A natural solution for alleviating inflammatory disorders.

Coumarin, a naturally occurring compound found in various plants, has a rich history of use in traditional medicine. Recent research has highlighted its anti-inflammatory properties, positioning it as a promising candidate for treating inflammatory disorders such as rheumatoid arthritis, asthma, and inflammatory bowel disease. This narrative review aims to comprehensively summarize the current knowledge regarding coumarin's pharmacological effects in alleviating inflammatory conditions by analyzing preclinical and clinical studies. The review focuses on elucidating the mechanisms through which coumarin exerts its anti-inflammatory effects, including its antioxidant activity, inhibiting pro-inflammatory cytokine production, and modulation of immune cell functions. Additionally, the paper addresses potential limitations of using coumarin, such as concerns about toxicity at high doses or with prolonged use. Before widespread clinical application, further investigation is needed to fully understand coumarin's potential benefits and risks.

Synthesis and characterization of aniline-based azo molecules: In vitro pharmacological and emission studies.

The present work involves the synthesis of novel dispersed mono-azo dyes using different coupling components and 2-methoxy-5-nitro aniline as amine through a simple and convenient diazo-coupling method. The structures of the newly synthesized mono azo dyes were confirmed by using various spectral techniques such as 1H NMR, Fourier transform infrared, and high-resolution mass spectrometry. At room temperature, the electronic absorption spectra and fluorescence spectra of the synthesized mono azo dyes were recorded with different solvents. The global reactive parameters for the synthesized azo molecules were evaluated by performing density functional theory through the 6-311++G (d, p) basis set. The anti-microbial activities for the synthesized azo compounds were carried out, and the compounds G1 and G2 exhibited good antibacterial and anti-fungal activities. The in silico molecular docking studies of the azo molecules revealed that all the compounds exhibited extraordinary binding affinity as that of the standard drug. Further, the anti-tuberculosis study against the Mycobacterium tuberculosis for the synthesized azo dyes was evaluated, and from the results, it was revealed that the compound G4 showed good sensitivity among the other synthesized azo compounds.

Effect of poly(ε-caprolactone) microspheres on population pharmacokinetic/pharmacodynamic model of a simple coumarin.

This study aims to evaluated the impact of poly(ε-caprolactone) (PCL) microspheres on the pharmacokinetics and pharmacodynamics (PopPK/PD) of 6-methylcoumarin (6MC). For this, PCL microspheres loaded with 6MC were prepared using the emulsification-evaporation method. Particle size, zeta potential, drug loading, and entrapment efficiency were characterised by dynamic light scattering and UV spectrophotometry. In vitro release and pharmacokinetics in Wistar rats were assessed for free and encapsulated 6MC. Anti-inflammatory activity was evaluated using the carrageenan-induced paw edoema model, with PopPK and PopPK/PD models developed. Microspheres showed diameters between 2.9 and 7.1 µm, zeta potentials of -10 to -15 mV, and drug loading of 0.24 mg/mg. Encapsulation efficiency was 45.5% to 75.9%. PopPK models showed enhanced absorption and distribution, with increased anti-inflammatory potency of encapsulated 6MC. PCL microspheres significantly improved the pharmacokinetic and pharmacodynamic profiles of 6MC, enhancing its therapeutic potential for lipophilic drugs.

Coumarin derivatives as therapeutic candidates: a review of their updated patents (2017-present).

INTRODUCTION: Coumarins constitute a family of heterocyclic compounds that have been extensively studied as possible drugs in the pharmaceutical research to support human health. AREAS COVERED IN THIS REVIEW: A survey of patent publications from 2017 to mid-2024, taken from Google Scholar, Web of Science, Scopus, or PubMed analyzes coumarins and their derivatives. It covers synthetic methods, hybridization techniques, and assessments of their biological effects in laboratory and biological studies, such as cytotoxic, antitumor, anticancer, cardiovascular, anti-atheromatic, antidiabetic, anti-asthmatic and antioxidant properties. Additionally, it presents and discusses several pharmaceutical applications for treatment and compositions involving these compounds. Structural activity relationships and mechanism of action are presented and discussed. EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability and drug-likeness, the mechanism of action in animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic technique outbalance in the discovery and production of coumarins with greater selectivity. Their clinical evaluation will be critical to assess therapeutic utility. The coumarins, for which extended biological investigations confirmed their mechanism of action, can serve as lead or hit structures for the design of new libraries with more potent molecules.

Coumarins rather than alkylamides evoke the numbing orosensation of pomelo peel.

Liangpingyou, a well-known Chinese pomelo (Citrus grandis L.) variety, elicits a unique and uncharacterized numbing aftertaste. To understand the molecular bases and characteristics of the pomelo-induced numbing sensation, we first determined that hydroxyl sanshools, the major Sichuan pepper chemosensates, were not responsible via silylation-GC-MS analysis. Pomelo peel juice was then subjected to solid-phase extraction to form 4 fractions, and key sensory-active substances were screened via taste dilution analysis. Three simple coumarins, meranzin hydrate, isomeranzin, and marmin, were identified to induce numbing, which has not been previously reported. Sensory studies via extensively modified half-tongue tests and verification steps revealed recognition thresholds within 0.49-1.78, 0.32-1.56, and 0.43-1.46 µmol/L for numbness, pungency, and astringency, respectively. The temporal dominance trends showed the following taste notes: Meranzin hydrate-numbing dominated, isomeranzin-numbing and pungent, and marmin-astringent and numbing. Molecular docking analysis suggested that coumarins target the receptors TRPV1, TPRA1, and KCNK3.

A comprehensive review on the potential of coumarin and related derivatives as multi-target therapeutic agents in the management of gynecological cancers.

Current treatments for gynecological cancers include surgery, radiotherapy, and chemotherapy. However, these treatments often have significant side effects. Phytochemicals, natural compounds derived from plants, offer promising anticancer properties. Coumarins, a class of benzopyrone compounds found in various plants like tonka beans, exhibit notable antitumor effects. These compounds induce cell apoptosis, target PI3K/Akt/mTOR signaling pathways, inhibit carbonic anhydrase, and disrupt microtubules. Additionally, they inhibit tumor multidrug resistance and angiogenesis and regulate reactive oxygen species. Specific coumarin derivatives, such as auraptene, praeruptorin, osthole, and scopoletin, show anti-invasive, anti-migratory, and antiproliferative activities by arresting the cell cycle and inducing apoptosis. They also inhibit metalloproteinases-2 and -9, reducing tumor cell migration, invasion, and metastasis. These compounds can sensitize tumor cells to radiotherapy and chemotherapy. Synthetic coumarin derivatives also demonstrate potent antitumor and anticancer activities with minimal side effects. Given their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold significant potential as therapeutic agents in gynecological cancers, potentially improving treatment outcomes and reducing side effects. This review will aid in the synthesis and development of novel coumarin-based drugs for these cancers.

Design, synthesis and biological evaluation of novel benzocoumarin derivatives as potent inhibitors of MAO-B activity.

The continued research of novel reversible inhibitors targeting monoamine oxidase (MAO) B remains crucial for effectively symptomatic treatment of Parkinson's disease. In this study we synthesized and evaluated a new series of 3-aryl benzo[g] and benzo[h] coumarin derivatives as MAO-B inhibitors. Compound A6 has been found to display the most potent inhibitory activity and selectivity against the MAO-B isoform (IC50 = 13 nM and SI = >7693.31 respectively). Inhibition mode of A6 on MAO-B was predicted as mixed reversible inhibition with a Ki value of 3.274 nM. Furthermore, in order to elaborate structure-activity relationships, the binding mode of A6 was investigated by molecular docking simulations.

Locomotor-Reducing, Sedative, and Antidepressant-Like Effects of Confectionery Flavours Coumarin and Vanillin.

Coumarin and vanillin are compounds with comforting scents and are often used for flavouring confectionery. The locomotor-reducing, sedative, and antidepressant-like effects of coumarin and vanillin vapours administered via inhalation were investigated. Coumarin and vanillin showed all these effects. In particular, antidepressant-like effects were observed over a wide range of doses and were stronger than the positive control, fluoxetine (10 mg/kg). These results suggest that coumarin and vanillin may be suitable as antidepressant-like agents without strict dose control.

Synthesis and investigation of selective human carbonic anhydrase IX, XII inhibitors using coumarins bearing a sulfonamide or biotin moiety.

The role of carbonic anhydrases isoforms (CAs) IX and XII in the pathogenesis and progression of many types of solid tumors is well known. In this context, selective CA inhibitors (CAIs) towards the mentioned isoforms is a validated strategy for the development of agents to target cancer. For this purpose, novel coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds were synthesized and tested as inhibitors of four different human carbonic anhydrases isoforms: hCA I, II, IX and XII. Coumarin-sulfonamide derived 27, with a thiourea moiety and triazole as linker, showed the highest inhibition activity against hCA XII with an inhibition constant (KI) of 7.5 nM and afforded a very good selectivity over hCA I. Compound 32 was the most potent inhibitor against hCA IX (KI = 6.3 nM), 4-fold stronger than the drug acetazolamide AAZ (KI = 25 nM), used herein as a reference compound, and showed remarkable selectivity over hCA I and II. The coumarin-biotin derivatives 37-39 showed outstanding selectivity towards on-target enzymes (hCA IX and XII) and appear as plausible leads for designing of CAIs.

Esculetin Combats Multidrug-Resistant Salmonella Infection and Ameliorates Intestinal Dysfunction via the Nrf2 Pathway.

The increasing incidence of multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Tm), known for causing invasive enteric infections, presents a significant public health challenge. Given the diminishing efficacy of existing antibiotics, it is imperative to explore novel alternatives for the treatment of MDR S. Tm infections. Here, we identified esculetin (EST), a natural coumarin abundant in dietary foods and herbs, as a compound exhibiting broad-spectrum antibacterial properties against a range of MDR bacteria. Our findings demonstrate that EST effectively inhibited the proliferation and expansion of MDR S. Tm in both in vitro experiments and animal models. Specifically, EST significantly downregulated the type 3 secretion system-1 (T3SS-1) virulence expression of MDR S. Tm, thereby preventing its invasion into intestinal epithelial cells. In S. Tm-infected mice, we observed cecal injury characterized by the upregulation of inflammatory cytokines, a reduction in goblet cell numbers, a decreased expression of tight junction proteins, and microbial dysbiosis. Conversely, EST treatment ameliorated these pathological changes induced by S. Tm infection and reduced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby improving intestinal barrier function. These results suggest that dietary coumarins or a targeted plant-based diet may offer a promising strategy to counteract MDR bacteria-induced enteric diseases.

Facile One-Pot Conversion of (poly)phenols to Diverse (hetero)aryl Compounds by Suzuki Coupling Reaction: A Modified Approach for the Synthesis of Coumarin- and Equol-Based Compounds as Potential Antioxidants.

A series of 16 (hetero)aryl compounds based on coumarin and equol has been efficiently synthesized by exploring the palladium-catalyzed Suzuki cross-coupling reactions. Polyphenol based on coumarin (4-methyl-7-hydroxy coumarin) was initially converted to corresponding coumarin imidazylate and then subjected to Suzuki coupling reaction with 4-methoxyphenylboronic acid to obtain the coupled product. This modified approach was later developed into a one-pot methodology by directly reacting the polyphenol with 1,1-sulfonyldiimidazole (SDI) and boronic acid in situ to obtain the Suzuki coupled product in one step. Moreover, an array of (poly)phenols based on coumarin and equol were later converted to diverse (hetero)aryl compounds by this optimized step-economic protocol. The synthesized compounds were then subjected to the screening of their potential antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In our investigation, the compounds 4ah, 4eh, 4gh and 4hh exhibited promising antioxidant potential when compared to the reference standard, butylated hydroxytoluene (BHT). Structure activity relationship (SAR) studies revealed the importance of the presence of electron-donating substituents in enhancing the antioxidant activity of the synthesized compounds.

Non-destructive visual detection of fresh food spoilage.

Two coumarin derivatives SWJT-33 and SWJT-34 were synthesized as probes for the detection of cadaverine (Cad). Among them, SWJT-34 exhibits high selectivity and low detection limits for Cad using fluorescence or UV-vis spectrum. The detection limits for Cad were calculated to be 0.018 µM by fluorescence spectrum and 0.34 µM by UV-vis spectrum, which was much lower than those of most of reported probes. The probe could realize colorimetric and ratiometric detection of Cad because an aza-Michael addition reaction occurred between SWJT-34 and Cad to form the Schiff base compound as a product. In addition, SWJT-34 could be fabricated as portable test strips for the selective detection of Cad in vapor, and the corresponding detection limits were calculated to be 1.88 ppm in the fluorescent mode and 57 ppm in UV-vis mode, respectively. Additionally, these test strips could be used to test the freshness of Rottweiler shrimp and pork at different temperatures.

A novel fluorescent probe based on coumarin derivatives-grafted cellulose for specific detection of Fe3+ and its application.

Fe3+ is one of the most important ions for maintaining the normal growth of plants and animals. However, imbalance and accumulation of Fe3+ can lead to serious damage to the environmental system. Hence, it is considerably crucial to monitor the concentration of Fe3+. In this paper, a high-performance fluorescent probe CA-NCC for specifically detecting Fe3+ was obtained by grafting cellulose acetate (CA) with coumarin derivative (NCC). The resulted probe displayed a bright blue fluorescence in THF solution and showed a distinct "turn-off" fluorescence response to Fe3+, while the small molecule compound NCC could not realize the detection of Fe3+. CA-NCC displayed excellent response performance to Fe3+ including excellent selectivity and sensitivity, rapid reaction time (2.5 min), wide pH detection range (6-11), and low detection limit (0.178 µM). More importantly, CA-NCC was successfully fabricated into fluorescent film based on the good processability of cellulose acetate, and achieved highly selective recognition of Fe3+ from various metal ions.

A novel dual-site fluorescent probe for the one-step detection of Cys and SO2 in living cells.

BACKGROUND: Cysteine (Cys) is the major intracellular thiol and plays a key role in human pathology. Furthermore, endogenous sulfur dioxide (SO2) is produced in mammals. Abnormal levels of SO2 are commonly associated with a variety of respiratory, cardiovascular, and neurological diseases. Therefore, given their important role in life activities, it is significant to construct a fluorescent probe that can detection between Cys and SO2. RESULTS: We have designed and synthesized a two-site fluorescent probe CUM with coumarin derivative and benzaldehyde molecules, which can detect and differentiate between Cys and SO2 through dual excitation wavelengths. Its carbon-carbon double bond reacts with Cys and undergoes a nucleophilic reaction, emitting green fluorescence at 520 nm, while SO32- reacts with benzaldehyde molecules in the probe CUM and undergoes a blue fluorescence at 460 nm. SO32- reacts with the benzaldehyde molecule of probe CUM and fluoresces blue at 460 nm. Thus, the probe CUM with two reaction sites can distinguish between Cys and SO2 and shows good selectivity and fast reaction speed. In addition, we successfully utilized probe CUM to image Cys and SO2 in human breast cancer cells (MDA-MB-231). SIGNIFICANCE: This work provides an effective method for the molecular design of coumarin-based fluorescent probes. Probe CUM as a promising and reliable tool for the meticulous discrimination and quantification of Cys and SO2 in diverse biological matrices, thereby opening up new avenues for various biological systems.

Novel förster resonance energy transfer (FRET)-based ratiometric fluorescent probe for detection of cyanides by nucleophilic substitution of aromatic hydrogen (SNArH).

The development of novel fluorescent probes for real-time detection of cyanides (CN-) in environmental and biological systems has become a significant focus in chemical sensing. Particularly, ratiometric fluorescence sensing offers a unique method for precise and quantitative detection of cyanides, even under complex conditions. We report herein the design of a new ratiometric fluorescent probe for cyanides based on modulation of Förster resonance energy transfer (FRET) coupled with novel cyanide-induced nucleophilic substitution of aromatic hydrogen (SNArH). The target probe (R1) is developed by introducing coumarin fluorophores as FRET donors into a 3-nitro-naphthalimide acceptor, which is easily synthesized and exhibits a colorimetric change from colorless to faint yellow and a significant ratiometric fluorescence shift (Δλ = 114 nm) upon cyanide binding. A clear ratiometric signal at I582/I468 was obtained, with a limit of detection of 5.69 µM. The sensing mechanism was confirmed through 1H NMR titration and LC-MS analysis. Additionally, R1-loaded strips were easily prepared, serving as a portable device for detecting CN- with visible color changes. The probe R1 has been successfully utilized for real-time monitoring of cyanide in food materials and water samples. Importantly, fluorescence bioimaging studies in HeLa cells were conducted, demonstrating the probe's capability for ratiometric detection of exogenous CN- in living systems.

Reactive Fluorescent and Colorimetric Probe for Highly Selective and Sensitive Detection of Hg2+ in Real Water Samples.

Construction of efficient chemosensors for highly specific and sensitive detection of mercury ions remains a great challenge. In this work a highly selective and sensitive probe CY was designed and synthesized by using coumarin fluorophore as the matrix and thioacetal moiety as the reactive recognition site for Hg2+. By virtue of the thiophilicity of Hg2+, probe CL could be hydrolyzed to deprotect and the thioacetal was transformed to the acyl group after the addition of Hg2+, the blue-green fluorescence was quenched and meanwhile the solution changed from light green to yellow. The detection limit of probe CY for Hg2+ was as low as 6.8 nM, and it could completely react with Hg2+ within 3 min. Moreover, probe CY exhibited good resistance against interference from competitive metal ions and biothiols, high stability in pH 1-11 and applicability for fluorogenic and chromogenic dual-modal detection of Hg2+ in real water samples over a broad range of pH 5-10.

A coumarin derivative C7 exhibits antiviral activity against WSSV by reducing phosphatidylcholine content in shrimp.

The white spot syndrome virus (WSSV) causes white spot disease (WSD), a severe condition in crustacean aquaculture, leading to significant economic losses. Our previous study demonstrated that C7 is an effective therapeutic agent against WSSV infection in aquaculture. It specifically blocked viral horizontal transmission and reduced shrimp mortality in a dose- and time-dependent manner. Here, we report the potential antiviral mechanism of C7 in shrimp. C7 regulated abnormal glycerophospholipid metabolism caused by WSSV and inhibited phosphatidylcholine (PC) synthesis by more than twofold, potentially enhancing shrimp resistance to viral infection. As the primary phospholipid in the cell membrane, PC is one of the main reactants in lipid peroxidation. Our results indicated that C7 significantly reduced the levels of lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) induced by WSSV, whereas PC had the opposite effect. Accumulation of lipid peroxidation products inhibits stimulator of interferon genes (STING) signaling. Further evidence showed that C7 promoted STING transport from the endoplasmic reticulum to the Golgi apparatus, significantly activating the expression of the shrimp interferon analogue Vago4 gene. In contrast, PC suppressed Vago4 expression. Our results demonstrated that C7 inhibited PC synthesis, reduced the degree of lipid peroxidation, promoted STING translocation, activated Vago4 expression, and ultimately exerted antiviral effects. Therefore, C7 exhibits immunoregulatory activity as a preventative agent for enhancing the innate immunity of shrimp, making it potentially useful for future immunomodulatory approaches.