Synthesized Coumarin Derivatives Research Articles

The inhibitory potential of 4,7-dihydroxycoumarin derivatives on ROS-producing enzymes and direct HOO•/o2 • – radical scavenging activity – a comprehensive kinetic DFT study

This study examined the antiradical activity of three synthesized coumarin derivatives: (E)-3-(1-((2-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A1-OH), (E)-3-(1-((3-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A2-OH), and (E)-3-(1-((4-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A3-OH) against HOO•/O2•− radical species. The investigation included electron spin resonance (ESR) measurements and a DFT kinetic study. Thermodynamic and kinetic parameters of antiradical mechanisms—Formal Hydrogen Atom Transfer (f-HAT), Radical Adduct Formation (RAF), Sequential Proton Loss followed by Electron Transfer (SPLET), and Single-Electron Transfer followed by Proton Transfer (SET-PT)—were evaluated using the Quantum Mechanics-based test for Overall Free Radical Scavenging Activity (QM–ORSA) under physiological conditions. ESR results indicated antiradical activity decreased in the sequence A1–OH (58.7%) > A2–OH (57.5%) > A3–OH (53.1%). Kinetic analysis revealed the f-HAT mechanism dominated HOO• inactivation. A newly formulated Sequential Proton Loss followed by Radical Adduct Formation (SPL-RAF) mechanism described interactions with O2 •−. The activity toward O2 •− was A2–OH (1.26 × 106 M−1s−1) > A3–OH (7.71 × 105 M−1s−1) > A1–OH (4.22 × 105 M−1s−1). Molecular docking and dynamics studies tested inhibitory capability against enzymes producing reactive species: Lipoxygenase (LOX), Myeloperoxidase (MPO), NAD(P)H oxidase (NOX), and Xanthine Oxidase (XOD). Affinity to enzymes decreased in the order: XOD > LOX > NOX > MPO.

Antibacterial Activity for Synthesized Coumarin Derivatives and a Coumarin Component of Lime Peel (Citrus aurantifolia).

In this study, we investigated the antibacterial activity of the coumarin component isolated from lime peel and coumarin derivatives synthesized using various techniques against eight types of food-poisoning bacteria. The minimum inhibitory concentration (MIC) for the 3b [5,7-dihydroxy-4-trifluoromethylcoumarin] derivative was measured as 1.5 mM in Bacillus cereus, Micrococcus luteus, Listeria monocytogenes, and Staphylococcus aureus subsp. aureus; that for the 3c [7-hydroxy-4-trifluoromethylcoumarin] derivative was 1.7 mM in Enterococcus facium; and that for the 3n [dicoumarol] derivative was 1.2 mM in L. monocytogenes. These results confirmed that coumarin derivatives with CF3 and OH substituents had enhanced antibacterial activity.

Effects of ethyl 7-hydroxy-2-imino-2H-chromene-3-carboxylate, a synthesized coumarin derivative, on bisphenol A-induced kidney toxicity

Aim: In this study, it was aimed to investigate the protective effect of the synthesized coumarin ethyl 7-hydroxy-2-imino-2H-chromene-3 carboxylate (CM) against the renal toxicity of Bisphenol A (BPA). Materials and Methods: The CM molecule was synthesised through the reaction between 2,4-dihydroxybenzaldehyde and ethyl cyanoacetate. Experiment was conducted in four groups of rats: control, BPA, CM, and BPA+CM. Total Antioxidant Status (TAS), Total Oxidant Status (TOS), and Malondialdehyde (MDA) levels in kidney tissue were evaluated. serum samples were analyzed for Total-Native thiol and kidney function test parameters. Results: The BPA-treated group exhibited significant decreases in TAS and thiol levels, increases in TOS and MDA levels. However, these side effects were significantly reduced with CM. Conclusion: results obtained in this study indicate that CM molecule has a protective effect against BPA induced kidney toxicity.

Unveiling of novel synthesized coumarin derivative for efficient self-driven hybrid organic/inorganic photodetector applications

During this study, a novel organic semiconductor material comprising coumarin and chromone moieties was synthesized via a facile route. Thin films of the synthesized powder were thermally deposited under vacuum conditions. The structural and morphological properties were investigated using X-ray diffraction and scanning electron microscope techniques, respectively. With increasing the film thickness, a relative crystallinity enhancement was observed, besides improving the surface features and uniformity. Furthermore, the UV–vis–NIR spectral transmittance and reflectance of the grown films were measured. The variation of film thickness induced significant changes in the optical parameters either dispersive or electronic such as energy gap (3.67–3.8 eV), oscillator energy (4.25–4.56 eV), and dispersion energy (4.61–10.31 eV). In addition, the nonlinear optical parameters and PL emission spectra of the prepared films were measured and analyzed in detail. Then, these films were exploited integrally with p-Si for the fabrication hybrid junction for light sensing. The optimized film thickness based on the optical, structure results, and electronic performance under dark conditions was ∼124 nm. Such a device showed a pronounced self-driven photodetection performance under different illumination intensities. The photoelectronic parameters including responsivity (∼5.17 mA/W), detectivity (∼2.64 × 1010 Jones), linearity (∼72.72 dB), and rise/fall times(∼51.48 ms/47.75 ms) were extracted and compared to other organic/p-Si devices and showed a high superiority.

The angiogenesis-modulating effects of coumarin-derivatives

Coumarin is a natural compound that is rich in plants. Coumarin and its derivates were reported to have many biological activities, such as anti-bacterial, anti-tumor, and anti-coagulation. In this study, we examined the angiogenic modulating activities of six previously synthesized coumarin derivatives (Compound #1-#6) in zebrafish embryos and further confirmed them in a chick model. According to the survival rate in a zebrafish model, Compound #1 (100 %), #2 (82.5–100 %), and #4 (100 %) showed much less toxicity than Compound #3 (19.2–100 %), #5 (0–100 %), and #6 (0–100 %). Using a green blood vessel fluorescent transgenic fish Tg(fli1:egfp) to record the angiogenesis-modulating effects of Compound #1, #2, and #4, we found that Compound #2 had the highest effects in interfering intersegmental vessel growth, subintestinal vein growth, and caudal vein plexus remodeling. Chick chorioallantoic membrane (CAM) assay also showed that Compound #2 exposure led to a reduction of blood vessel growth. Real-time PCR experiments revealed that Compound #2 significantly changed the expression of vascular growth-related genes flt1, cdh5, and nrp1a in zebrafish. Based on our data from zebrafish and chick models, a new coumarin-derivative (Compound #2) possesses anti-angiogenic activity with low toxicity, but further investigation in mammal models is asked to confirm our findings.

Multimodal antibacterial potency of newly designed and synthesized Schiff's/Mannich based coumarin derivatives: potential inhibitors of bacterial DNA gyrase and biofilm production.

The briskened urge to develop potential antibacterial candidates against multidrug-resistant pathogens has motivated the present research study. Herein, newly synthesized coumarin derivatives with azomethine and amino-methylated as the functional groups have been focused on their antibacterial efficacy. The study proposed two distinct series: 3-acetyl substituted coumarin derivatives, followed by the Schiff base approach (5a-5i), and formaldehyde-secondary cyclic amine-based derivatives (7a-7g), using the Mannich base approach, further the compounds have been confirmed through various spectral studies. Further, target-specific binding affinity has been affirmed via in silico study. In vitro antibacterial study suggested compounds 5d and 5f to be most effective against S. aureus and multidrug-resistant K. pneumoniae, with MIC values of 8 and 16 μg mL-1. Among them, the compounds 5d and 5f showed excellent binding scores against different bacterial gyrase compared to the standard novobiocin. Based on RMRS, RMSF, Rg, and H-bond plots, MD simulation study at 100 ns also suggested better stability of 5d inside gyraseB of E. coli than the complex of E. coli-GyrB-novobiocin. The toxicity and pharmacokinetic profiles showed favorable drug-likeness. Overall, systematic in vitro and in silico assessment suggested that multimodal antibacterial derivatives 5d and 5f strongly inhibit both bacterial DNA gyrase and biofilm formation of drug-resistant pathogens, suggesting their potency in mainstream antibacterial therapy.

Investigation of novel radical scavenging mechanisms in the alkaline environment: Green, sustainable and environmentally friendly antioxidative agent(s)

Pharmaceutical and industrial utilization of synthetic chemicals has an immerse impact on the environment. In that sense, novel chemicals with potential for industrial application should be investigated for their behaviour in reactions with hydroxyl radical, simulating AOPs (Advanced Oxidation Processes). AOPs are known for being highly effective in wastewater management and natural water remediation. In this paper, exhaustive research on the radical scavenging activity of a newly synthesized coumarin derivative (4HCBH), as a representative of the series of coumarin-benzohydrazides with high antioxidative potential was conducted. This study took into consideration the pH value range significant for practically all living organisms (pH = 7.0–8.5). According to the experimentally obtained results, the 4HCBH showed an increase in radical scavenging activity, following the slight increase in pH values, which suggested that the formation of anionic form of 4HCBH is responsible for its antiradical activity. Further investigations led to the postulation of a novel mechanistic approach called Sequential Proton Loss Electron Transfer – Radical-Radical Coupling (SPLET-RRC), in which, by a series of steps, a new, stable compound was formed. Furthermore, it was demonstrated that the product generated through SPLET-RRC showed lower toxicity than the parent molecule.

Structural properties of newly 4,7-dihydroxycoumarin derivatives as potential inhibitors of XIIa, Xa, IIa factors of coagulation

Some coumarin derivatives show notable anticoagulant properties through their ability to interrupt the enzymatic function of vitamin K epoxide reductase. The current challenge lies in the development of novel derivatives that are more efficient and less harmful, specifically targeting the direct inhibition of coagulation factors. This study examined the direct inhibitory potential of two recently synthesized coumarin derivatives, 3-(1-(3-hydroxy-4-methoxyphenyl)-amino)-ethyldiene)-2,4-dioxochroman-7-yl acetate (A-3OH) and 3-(1-(4-hydroxy-3-methoxyphenyl)-amino)-ethyldiene)-2,4-dioxochroman-7-yl acetate (A-4OH), according to coagulation factors IIa, Xa, and XIIa. Accurately defining the structural properties of compounds is of great importance for a comprehensive understanding of the biological activity of pharmaceutical agents. In regard, this study aimed to analyze the structural (Potential Energy Surface (PES)), spectroscopic (FT-IR, NMR, and UV–Vis), and electronic properties (Quantum Theory of Atoms in Molecules (QTAIM)) of two newly synthesized compounds. These properties are determined using a combination of experimental and theoretical methods (B3LYP-D3BJ/6–311++G(d,p) level of theory). The investigated compounds deviate from planarity based on the results of structural properties. The results of QTAIM analysis show the presence of partially covalent hydrogen bonds and closed-shell van der Waals interactions that stabilize the examined compounds. Based on the large correlation coefficient (R) and low mean absolute error (MAE) of the spectroscopic data showed that the applied level of theory effectively replicated the experimental finding. The results from the molecular docking study suggest that both compounds demonstrate similar inhibitory effects on IIa when compared to the standard inhibitor dabigatran (DAB). The efficacy of A-3OH in inhibiting Xa is similar to that of conventional inhibitors apixaban (API), and rivaroxaban (RIV). The observed inhibitory effect of both compounds on coagulation factor XIIa was more potent than that of the conventional co-crystallized inhibitor. The results of this study add to the understanding of the structure-activity relationship of coumarin derivatives and provide possibilities for enhancing anticoagulant therapy and clinical outcomes for coagulation-related illnesses. The findings lay a foundation for further in vitro and in vivo investigations into the anticoagulant activities of the compounds, contributing to their potential pharmaceutical application.

Anti-Alzheimer potential of coumarin derivatives: A review

Alzheimer’s is a type of neurodegenerative diseases (NDs) found in old age people which main causes the dementia and various brain disorders. FDA approved drugs used commonly in treatment of moderate to severe Alzheimer's disease are Donepezil, Rivastigmine, Galantamine and Memantine. However, these approved drugs provide only palliative support not complete cure. So, urgency of new molecules has been becoming so important to cure this complex Disease. Coumarin or 2-H-Chromen-2-one is an oxygenated heterocyclic compound, which is isolated from plants named Dipteryx odorata Willd, (Fabaceae). Synthetic coumarin derivatives has been well presence in literature due to existence of their potential pharmacological activities in literature. This review covers the anti-Alzheimer activities of chemically synthesized coumarin derivatives from 2016-2023. Coumarin derivatives profound found exhibits potential anti-Alzheimer activities in literature. Coumarin derivatives showed their anti-Alzheimer potential through various pharmacological pathways such as monoamine oxidase (MAO) inhibitor, acetylcholinesterase (AChE) & Butyl cholinesterase (BuChE) inhibitory activity, Aβ amyloid inhibition, Beta secretase 1 (BACE1 inhibitors). Multi-target directed ligands (MTDLs) approach also extensively reported to design and synthesis of novel coumarin scaffold as potential multifunctional Anti-Alzheimer activities in last one decade. We also covered literature of some coumarin hybrids derivatives as potential Anti-Alzheimer activities. Some common synthetic methods of coumarin structure also covered in this review article. This review supported that coumarin derivatives found excellent anti-Alzheimer activities and it can be play major role to solve the problem of complex AD disease.

Synthesis of New Coumarin Scaffold Bearing 2-Iminochromene Moiety

Coumarin is classified as one of interesting therapeutic starting research points to obtain remarkable compounds with high efficacy. So, during this research, new 2-iminochromene derivatives bearing coumarin moiety were synthesized. At first, cyanoacetohydrazone of 3-acetylcoumarin was prepared and used as the starting material. The 2-iminochromene derivatives were synthesized through the ring closure of cyanoacetohydrazone derivative with 4-hydroxysalicylaldehyde, 5-aryldiazosalicylaldehydes, 2-hydroxynaphthaldehyde and 7-hydroxychromone-6-carboxaldehyde derivative. All of the newly synthesized coumarin derivatives were obtained in excellent yields; so, the new synthesized coumarin derivatives will participate in the enrichment of the chemical libraries.

In silico evaluation of pharmacokinetic parameters, delivery, distribution and anticoagulative effects of new 4,7-dihydroxycoumarin derivative

In this study, pharmacological profiling and investigation of the anticoagulant activity of the newly synthesized coumarin derivative: (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (L) were performed. The obtained results were compared with the parameters obtained for Warfarin (WF), which is a standard good oral anticoagulant. The estimated high binding affinity of L toward plasma proteins (PPS% value is > 90%) justifies the investigation of binding affinity and comparative analysis of L and WF to Human Serum Albumin (HSA) using the spectrofluorimetric method (296, 303 and 310 K) as well as molecular docking and molecular dynamics simulations. Compound L shows a very good binding affinity especially to the active site of WF (the active site I -subdomain IIA), quenching HSA fluorescence by a static process. Also, the finite element smeared model (Kojic Transport Model, KTM), which includes blood vessels and tissue, was implemented to compute the convective-diffusion transport of L and WF within the liver. Finally, compound L shows a high degree of inhibitory activity toward the VKOR receptor comparable to the inhibitory activity of WF. Stabilization and limited flexibility of amino acid residues in the active site of the VKOR after binding of L and WF indicates a very good inhibitory potential of compound L. The high affinity of the L for the VKOR enzyme (Vitamin K antagonist), as well as the structural similarity to commercial anticoagulants (WF), provide a basis for further studies and potential application in the treatment of venous thrombosis, pulmonary embolism and ischemic heart disease. Communicated by Ramaswamy H. Sarma

NMR-Based Metabolomics to Analyze the Effects of a Series of Monoamine Oxidases-B Inhibitors on U251 Cells.

Alzheimer's disease (AD) is a typical progressive neurodegenerative disorder, and with multiple possible pathogenesis. Among them, coumarin derivatives could be used as potential drugs as monoamine oxidase-B (MAO-B) inhibitors. Our lab has designed and synthesized coumarin derivatives based on MAO-B. In this study, we used nuclear magnetic resonance (NMR)-based metabolomics to accelerate the pharmacodynamic evaluation of candidate drugs for coumarin derivative research and development. We detailed alterations in the metabolic profiles of nerve cells with various coumarin derivatives. In total, we identified 58 metabolites and calculated their relative concentrations in U251 cells. In the meantime, the outcomes of multivariate statistical analysis showed that when twelve coumarin compounds were treated with U251cells, the metabolic phenotypes were distinct. In the treatment of different coumarin derivatives, there several metabolic pathways changed, including aminoacyl-tRNA biosynthesis, D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, glutathione metabolism and valine, leucine and isoleucine biosynthesis. Our work documented how our coumarin derivatives affected the metabolic phenotype of nerve cells in vitro. We believe that these NMR-based metabolomics might accelerate the process of drug research in vitro and in vivo.

Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR-2 and DNA gyrase inhibition, and in silico studies.

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 μg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a-c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.

Synthesis of Novel Bis-Coumarin Derivatives as Potential Acetylcholinesterase Inhibitors: An In Vitro, Molecular Docking, and Molecular Dynamics Simulations Study

Background: Alzheimer disease is a progressive and irreversible disease that finally leads to death. It destroys cognitive skills and memory, and eventually, the patient cannot do the simplest things.
 Objectives: Cholinesterases (ChEs) which has the capability to control cholinergic transmission would result in elevating acetylcholine levels in the brain, by inhibiting CHEs. Coumarins have been shown to exhibit the inhibitory effect of cholinesterase, where the aromatic component results in designing novel candidates that can inhibit Ab accumulation.
 Methods: The condensation of aryl aldehydes and 4-hydroxycoumarin. Besides, we applied ZnO nanoparticles as an effective heterogeneous catalyst in [bmim]BF4 . To determine the inhibitory activity, we used a substrate, i.e., acetylthiocholine iodide, to assay the tested compounds. Moreover, we applied Ellman’s assay.
 Results: The present research is an in vitro work. It explores the possible binding mode of these compounds inside the Acetylcholinesterase (AChE) enzyme. Moreover, regarding the synthesized coumarin derivatives, we also performed docking and Molecular Dynamics (MD) simulation studies. The results indicate a satisfactory inhibitory activity for the assayed compounds against AChE with IC50 values from 0.100 to 0.02 µM. In this sense, the stability of protein-ligand complexes and the interaction of the compounds can be understood by performing a molecular docking with molecular dynamics simulation of 5000 ps in the solvent system for AChE.
 Conclusion: Finally, it is worth mentioning that we also tested coumarin derivatives (L14 and L15), leading to potent and effective AChE inhibitors.

Cytogenotoxicity assessment of 3-(3,4-dihydroxyphenyl)-7,8-dihydroxycoumarin on HepG2/C3A cells and leukocytes.

3-(3,4-Dihydroxyphenyl)-7,8-dihydroxycoumarin is a newly synthesized coumarin derivative with a potent antioxidant effect. The aim of the present study is to investigate the safety of this compound, determining the in vitro cytotoxic and genotoxic in human peripheral blood mononuclear cells (PBMC) and in HepG2/C3A cells. Cell viability has been investigated by the trypan blue staining test and MTT assay and the genotoxicity by the comet assay and micronucleus test, using concentrations between 0.01 and 10 μg/ml. The compound proved to be noncytotoxic in both cell lines, at all tested concentrations, protecting the cells from the DNA damage. In addition, this molecule does not show clastogenic/aneugenic effects when performing the micronucleus test with cytokinesis blockade. Based on the obtained data, and the conditions of the experiments, we can conclude that the 3-(3,4-dihydroxyphenyl)-7,8-dihydroxycoumarin is a safe molecule up to a concentration of 10 μg/ml, which encourages further studies aiming to explore its potential as a drug candidate.

Microwave-promoted Synthesis and Optoelectronic Properties of Ethoxycarbonyl-substituted Coumarin and Benzo[f]coumarin

Microwave-assisted potassium fluoride-catalyzed synthesis of coumarin derivatives via tandem Knoevenagel condensation and intramolecular cyclization was established under solvent-free conditions. Satisfactory product yields were obtained with 67.87 and 90.21% as the highest recorded yields for the target compounds 3a (ethyl 2-oxo-2H-chromen-3-carboxylate) and 3b (ethyl 2-oxo-2H-benzo[f]chromen-3-carboxylate), respectively. The changes in the optoelectronic properties of the synthesized coumarin derivatives relative to the parent coumarin (2H-chromen- 2-one) molecule were also characterized to study, to some degree, the structure-to-property relationship of the compounds. Generally, extending the π-conjugation at position-3 by adding the ethoxycarbonyl group and expanding the π-system of the coumarin molecule at position-f shifts the absorption maxima to longer wavelengths, decreases the HOMO-LUMO energy band gap, and increases the light absorptivity of the coumarin compound.

In vitro Evaluation (Antioxidant Activity) of coumarin derivatives

Coumarin is a heterocyclic molecule associated with beneficial human health effects such as to reduce the risk of cancer, diabetes, cardiovascular and brain disease. These effects are thought to be related to free radical scavenging due to their antioxidant properties. Coumarin is a substance that has been synthesized in many of its derivatives in recent years. This entity is a major source of interest for many medicinal chemists to explore its various pharmacological possibilities, especially anticoagulant activity. The antioxidant activities of two synthesized coumarin derivatives namely 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N'-(1-(4-aminophenyl)ethylidene) acetohydra zide [M1] and 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N'-(1-(2 hydroxy phenyl) ethylidene) acetohydrazide [M2] were studied with the DPPH method. Structure of two coumarin synthesized compounds is proposed on the basis of spectroscopic evidence.

Evaluation of binding affinity of synthesized coumarin derivative on single-stranded DNA by spectroscopic methods

هدف: باتوجه به اهمیت مشتقات کومارین به‏عنوان داروی موثر بر سلول‏های سرطانی و اثرات درمانی متنوع دیگر، در این پژوهش بررسی تاثیر مشتق جدیدی از کومارین به‏نام 3-(تترازول-5-ایل) کومارین به DNA تک رشته در محلول با استفاده از روش‏های مختلف اسپکتروسکوپی مورد مطالعه قرار دادیم.مواد و روش‏ها: مطالعه حاضر به‏بررسی اثر 3-(تترازول-5-ایل) کومارین بر DNA تک رشته در شرایط آزمایشگاهی پرداخته است. نتایج حاصل نشان می‏دهد که میزان روند جذب DNA تک رشته در اثر میان‏کنش با 3-(تترازول-5-ایل) کومارین در طول موج‏های 210 و 260 نانومتر افزایش می‏یابد. طیف نشری DNA تک رشته در یک روند وابسته به غلظت 3-(تترازول-5-ایل) کومارین افزایش می‏یابد، که نشان‏دهنده اتصال 3-(تترازول-5-ایل) کومارین با کروموفورهای موجود در DNA تک رشته است.نتایج: اتصال 3-(تترازول-5-ایل) کومارین به DNA تک رشته‏ای سبب افزایش قابل توجه ellipticity در دورنگ ‏نمایی دورانی ملکول DNA در نواحی 220 و 275 نانومتر و مثبت‏تر شدن آن در 245 نانومتر می‏شود. نتایج حاکی از اتصال قوی تر داروی 3-(تترازول-5-ایل) کومارین به DNA تک رشته می‏باشد که می‏تواند به‏این‏دلیل باشد که احتمالا DNA تک رشته در هنگام همانندسازی بیش‏تر در دسترس است.نتیجه‏گیری: نتایج به‏دست آمده از اثر کومارین 3-(تترازول-5-ایل) برروی DNA تک رشته‏ای می‏تواند اطلاعات مفیدی در زمینه طراحی داروهایی با مشتقات کومارینی با اثر ضدتوموری بیش‏تر و عوارض جانبی کم‏تری در اختیار قرار دهد.

Antihypoxic effect of new synthetic derivatives of 7-alkoxycoumarin and 4-aminocoumarin in acute hypobaric hypoxia in rats

BACKGROUND: Coumarins are naturally occurring molecules with a wide range of pharmacological activities. Their use is limited by difficulties in isolation from plant material, toxicity, and low solubility. The chemical structure of these compounds makes coumarins promising for the synthesis of a large number of derivatives that may have biological activity and be of interest as potential drugs. We had synthesized coumarin derivatives, two of which IEM-2266 (7-alkoxycoumarin derivative) and IEM-2267 (4-aminocoumarin derivative) have shown antihypoxic effect in mice in models of hypoxic hypoxia with hypercapnia, histotoxic and hemic hypoxia.
 AIM: The aim of this work was to study the antihypoxic effect of new coumarin derivatives IEM-2266 and IEM-2267 under conditions of acute hypobaric hypoxia in rats.
 METHODS: The experimental work was performed on male Wistar rats weighing 200220 g. Acute hypobaric hypoxia was induced in rats by placing them in a flow pressure chamber. Compounds IEM-2266 and IEM-2267 were administered intraperitoneally at the dose 25 mg/kg once 50 minutes before hypoxia. Mexidol at the dose of 100 mg/kg was used as a reference drug. The antihypoxic activity of the substances was assessed according to the following indicators: 1) lifespan at the critical height 11,000 m; 2) the value of the individual high-altitude threshold; 3) individual resistance to hypoxia calculated from high-altitude threshold, expressed in points; 4) survival at consistently presented heights; 5) determination of the structure of population resistance according to the ratio of animals with low, medium and high resistance to hypoxia.
 RESULTS: New coumarin derivatives IEM-2266 and IEM-2267 exhibited antihypoxic activity under acute hypobaric hypoxia conditions. With the use of IEM-2266, IEM-2267, and Mexidol, the lifespan of animals at a critical altitude of 11,000 m increased by 2.4, 5.4, and 4.9 times, respectively, compared with the control, the point based assessment of individual resistance to hypoxia increased by 36, 66 and 67%, the absolute value of high-altitude threshold increased significantly (p 0.05). Coumarin derivatives changed the structure of population resistance, increasing the proportion of highly resistant animals.
 CONCLUSIONS: Thus, the effect of IEM-2267 is comparable, and even exceeds the effect of Mexidol. The 7-alkoxycoumarin derivative IEM-2266 has a moderate, and the 4-aminocoumarin derivative IEM-2267 has high antihypoxic activity in rat AHbH conditions.

Highly efficient inhibition of infectious hematopoietic necrosis virus replication mediated by a novel synthesized coumarin derivative in vitro and in vivo

As an efficient pathogen resulting in economic impact in aquaculture, infectious hematopoietic necrosis virus (IHNV) causes devastating disease in salmons. In this study, we designed and synthesized a novel coumarin derivative, 7-((4-aminophenyl)diazenyl)-4-methyl-coumarin (AMC), to evaluate its in vitro and in vivo anti-IHNV effects. The results showed that up to 25 mg/L AMC inhibited the expression of six IHNV protein genes in epithelioma papulosum cyprini (EPC) cells, with a maximum inhibitory rate of >90%. Furthermore, AMC inhibited EPC cell apoptosis induced by IHNV and kept the normal cellular morphological structure, reflecting in the protection of EPC cells from cell swelling, the formation of apoptotic bodies, the disappearance of cellular morphology and nuclear fragmentation. For in vivo study, AMC exhibited an anti-IHNV effect in the virus-infected fish by substantially enhancing the survival rate. Consistent with above results, AMC repressed IHNV gene expression in virus sensitive tissues (brain, kidney and spleen) in the early stage of virus infection. Meanwhile, up-regulation of four interferon (IFN) related gene expressions demonstrated that AMC may activate IFN-related expressions for inhibiting IHNV replication during the early stage of viral infection, which is beneficial for the continuous antiviral action on controlling low viral loads in rainbow trout juvenile. Thus, AMC effectively regulated IHNV-induced undesirable conditions to be an excellent potential therapeutic agent against IHNV infection.