Simple Coumarins Research Articles

Coumarins inhibit η-class carbonic anhydrase from Plasmodium falciparum

Coumarins were discovered to act as inhibitors of α-carbonic anhydrases (CAs, EC 4.2.1.1) after undergoing hydrolysis mediated by the esterase activity of the enzyme to the corresponding 2-hydroxycinnamic acids. Other classes of CAs among the eight currently known do not possess esterase activity or this activity was poorly investigated. Hence, we decided to look at the potential of coumarins as inhibitors of the η-CA from the malaria-producing protozoan Plasmodium falciparum, PfaCA. A panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system acted as low to medium micromolar PfaCA inhibitors, whereas their affinities for the cytosolic off-target human isoforms hCA I and II were in a much higher range. Thus, we confirm that η-CAs possess esterase activity and that coumarins effectively inhibit this enzyme. Elaboration of the simple coumarin scaffolds investigated here may probably lead to more effective PfaCA inhibitors.

A Review of Plants with Remarkable Hepatoprotective Activity

Liver being vulnerable to exogenous substances makes disease associated with it a matter of worldwide concern. Several research thus focus on hepatoprotection .Preventive and therapeutic activity of plants as a hepatoprotective agent is a topic of interest for researchers. Hepatotoxic agents like carbon tetrachloride, paracetamol, isoniazide etc. increase the serum biomarkers of liver where ALT is more specific than AST in detecting liver injury. Drug-induced liver injury (DILI) wherein more than 900 drugs have been implicated in causing liver injury. Plant phenolics include simple phenols, phenolic acids, coumarins, lignans, flavonoids, diaryl-alkanoids, stilbenoids, proanthocyanins, tannins, and anthocyanins some alkaloids. The greater the content of alkaloids, flavonoids, and saponins in an extract, the higher the hepatoprotective activity possessed by the extract. This paper reviews some plants documented between the periods of 2011-2021 with remarkable heptoprotective activity and discusses the various hepatotoxic agents used, its mechanism and hepatoprotective agents present in the specific plant.
 Keywords: Hepatoprotective plants, flavonoids, saponin, alkaloids,hepatotoxicity, drug induced liver injury, hepatotoxic agents

Natural Coumarin-Lead Compounds: A Review of Their Medicinal Potentials

Background: Natural coumarins group, a principal member of the benzopyrone family, is one of the naturally occurring substances obtained ordinarily from plant origins, with antibacterial, anticoagulant, antihypertensive, anticancer, antioxidant, anti-inflammatory, and many other medicinal potentials. Because coumarins are found in nuts, seeds, fruits, vegetables, tea, coffee, and wine, the average person consumes a significant amount of these substances daily. Given the documented limited toxicity, relatively cheap, availability in foods, and prevalence of coumarins in numerous herbal medicines, it seems reasonable to investigate their characteristics and usage.Objective: This review discusses naturally occurring coumarin lead substances, their extensive medicinal benefits, and official pharmacopoeia-based detection methods.Conclusion: The medicinal potential and therapeutic uses of simple coumarins are determined by their structural substitution pattern. Because there is limited research on bioavailability for coumarins, additional research is needed to investigate the bioavailability for various coumarins, which have demonstrated good bioactivity in prior research.

Coumarins effectively inhibit bacterial α-carbonic anhydrases

Coumarins are known to act as prodrug inhibitors of mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) but they were not yet investigated for the inhibition of bacterial α-CAs. Here we demonstrate that such enzymes from the bacterial pathogens Neisseria gonorrhoeae (NgCAα) and Vibrio cholerae (VchCAα) are inhibited by a panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system. The nature and the position of the substituents in the coumarin ring were the factors which strongly influenced inhibitory efficacy. NgCAα was inhibited with KIs in the range of 28.6–469.5 µM, whereas VchCAα with KIs in the range of 39.8–438.7 µM. The two human (h)CA isoforms included for comparison reason in the study, hCA I and II, were less prone to inhibition by these compounds, with KIs of 137–948.9 µM for hCA I and of 296.5–961.2 µM for hCA II, respectively. These findings are relevant for discovering coumarin bacterial CA inhibitors with selectivity for the bacterial over human isoform, with potential applications as novel antibacterial agents.

Mechanochemical synthesis of coumarins via Pechmann condensation under solvent-free conditions: an easy access to coumarins and annulated pyrano[2,3-f] and [3,2-f]indoles

A green protocol has been developed for the synthesis of simple coumarins and linear pyrano[2,3-f] and [3,2-f]indoles by the reaction of phenol derivatives with β-ketoesters under ball milling at ambient temperature in the presence of methanesulfonic acid.

Chemical constituents from the roots of Peucedanum praeruptorum Dunn and their chemotaxonomic significance

Chemical investigation on the roots of Peucedanum praeruptorum Dunn afforded 15 compounds, including five linear furocoumarins (1–5), six angular pyranocoumarins (6–11), two simple coumarins (12 and 13), a benzaldehyde derivative (14), and a phenylpropanoid glycoside (15). The structures of these compounds were established via spectroscopic analysis and comparison of their NMR data with the literature. Compound 1 was a new linear furocoumarin glycoside, while compounds 10–12, 14 and 15 were isolated from P. praeruptorum for the first time. The chemotaxonomic significance of these isolated compounds was summarized herein.

Optimization and application of green solvent extraction of natural bioactive coumarins from Lamiaceae and Asteraceae herbal plants

Simple coumarins, 2H-1-benzopyran-2-ones, represent group of natural bioactive compounds. They are considered as secondary metabolites in plants of Lamiaceae and Asteraceae families. In this study, heat assisted extraction with low transition temperature mixtures (LTTM) based on choline chloride and L-lactic acid were used for simultaneous extraction of esculin, umbelliferone, scoparone, 4-methylumbelliferone and herniarin from herbal plants prior their determination by HPLC method with fluorescence detection. The effect of LTTM composition on coumarins extraction was verified. Optimal extraction conditions included choline chloride/L-lactic acid/1,3-propanediol (1:2:1) extraction solvent, solid/liquid ratio 1/40 g/mL, treatment time 15 min, rotation speed 20 rpm and temperature 60 °C. Temperature was the most significant parameter affecting extraction efficiency, the extraction time was an important variable for penetration of solvent in the matrix. Proposed HPLC method was applicable in linear concentration ranges from 5 to 100 ng/mL (for esculin, umbelliferone, scoparone, 4-methylumbelliferone) and from 15 ng/mL to 100 ng/mL (for herniarin) (R2 ≥ 0.998). The limits of detection were 0.2–5.0 ng/mL. The recovery of the method was higher than 87.7% (RSD < 5.8%). The content of umbelliferone and herniarin in herbal plants were 11.49–68.38 μg/g. The use of LTTM extraction solvent, application the response surface methodology and Taguchi orthogonal arrays design of experiment for optimization of extraction conditions, were contribute to the green aspect of the developed method.

Identification and Quantification of Coumarins by UHPLC-MS in Arabidopsis thaliana Natural Populations.

Coumarins are phytochemicals occurring in the plant kingdom, which biosynthesis is induced under various stress factors. They belong to the wide class of specialized metabolites well known for their beneficial properties. Due to their high and wide biological activities, coumarins are important not only for the survival of plants in changing environmental conditions, but are of great importance in the pharmaceutical industry and are an active source for drug development. The identification of coumarins from natural sources has been reported for different plant species including a model plant Arabidopsis thaliana. In our previous work, we demonstrated a presence of naturally occurring intraspecies variation in the concentrations of scopoletin and its glycoside, scopolin, the major coumarins accumulating in Arabidopsis roots. Here, we expanded this work by examining a larger group of 28 Arabidopsis natural populations (called accessions) and by extracting and analysing coumarins from two different types of tissues–roots and leaves. In the current work, by quantifying the coumarin content in plant extracts with ultra-high-performance liquid chromatography coupled with a mass spectrometry analysis (UHPLC-MS), we detected a significant natural variation in the content of simple coumarins like scopoletin, umbelliferone and esculetin together with their glycosides: scopolin, skimmin and esculin, respectively. Increasing our knowledge of coumarin accumulation in Arabidopsis natural populations, might be beneficial for the future discovery of physiological mechanisms of action of various alleles involved in their biosynthesis. A better understanding of biosynthetic pathways of biologically active compounds is the prerequisite step in undertaking a metabolic engineering research.

Study on fragmentation patterns of coumarins in Notopterygium inchum with ultrahigh performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry

To demonstrate the fragmentation patterns of simple coumarins furanocourmarin(C_7-C_8), furanocourmarin(C_6-C_7) and dihydrofuran coumarin by mass spectrometry, with fraxin, scopoletin, isopsoralen, pimpinellin, isoimperatorin, notopterol and noda-kenin as study subjects, so as to provide a basis for rapid identification of compounds in different subtypes of coumarins. Ultrahigh performance liquid chromatography combined with quardrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was implemented in both positive and negative ion modes. Masslynx software was employed to provide the elemental constituents of each detected ion based on its accurate molecular weight. Chemdraw 2014 was used to cultivate mass number of each inferred structure. The fragment pattern of each compound was determined based on the structures inferred from all the relevant ions. And the patterns were drawn by Chemdraw 2014. The deviation between the calculated molecular weight of the inferred structure and the detected value of the ions was used to assess the correctness of the inferred structures in the fragmentation patterns. The results showed that with UPLC-Q-TOF, neutral loss of CO_2 and CO was reflected in lactone and furan skeletons from the courmarin structure. An even mass was attributed to the loss of an odd number of methyl radicals from compounds with a methoxy substituent. Furanocourmarin(C_7-C_8) produced a protonated molecular ion([M+H]~+), while the other courmarin subtypes produced either a sodium adduct of the molecular ion([M+Na]~+) or a sodium adduct of the molecular ion([M+Na]~+) with a protonated molecular ion([M+H]~+). The m/z 203.03 was a diagnostic ion for furanocourmarin(C_6-C_7), and the m/z 147.04 was supplementary evidence for furanocourmarin(C_6-C_7) identification. The characteristic ion of furanocourmarin(C_7-C_8) was m/z 131.05, while m/z 187.04 was the characteristic ion of dihydrofuran coumarin. The m/z 203.03 ion for furanocourmarin(C_7-C_8) was pretty weak. In negative ion mode, furanocourmarin(C_7-C_8) did not have any signals that were different from the other subtypes of courmarins. The fragmentation patterns in negative ion mode for the other subtypes of courmarins were similar to those in positive ion mode. Four types of fragmentation patterns were identified as forcourmarins from Notopterygium inchum. This study provides the basis for the rapid identification of courmarin subtypes by mass spectrometry.

Antiglioma Potential of Coumarins Combined with Sorafenib.

Coumarins, which occur naturally in the plant kingdom, are diverse class of secondary metabolites. With their antiproliferative, chemopreventive and antiangiogenetic properties, they can be used in the treatment of cancer. Their therapeutic potential depends on the type and location of the attachment of substituents to the ring. Therefore, the aim of our study was to investigate the effect of simple coumarins (osthole, umbelliferone, esculin, and 4-hydroxycoumarin) combined with sorafenib (specific inhibitor of Raf (Rapidly Accelerated Fibrosarcoma) kinase) in programmed death induction in human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells lines. Osthole and umbelliferone were isolated from fruits: Mutellina purpurea L. and Heracleum leskowii L., respectively, while esculin and 4-hydroxycoumarin were purchased from Sigma Aldrich (St. Louis, MO, USA). Apoptosis, autophagy and necrosis were identified microscopically after straining with specific fluorochromes. The level of caspase 3, Beclin 1, PI3K (Phosphoinositide 3-kinase), and Raf kinases were estimated by immunoblotting. Transfection with specific siRNA (small interfering RNA) was used to block Bcl-2 (B-cell lymphoma 2), Raf, and PI3K expression. Cell migration was tested with the wound healing assay. The present study has shown that all the coumarins eliminated the MOGGCCM and T98G tumor cells mainly via apoptosis and, to a lesser extent, via autophagy. Osthole, which has an isoprenyl moiety, was shown to be the most effective compound. Sorafenib did not change the proapoptotic activity of this coumarin; however, it reduced the level of autophagy. At the molecular level, the induction of apoptosis was associated with a decrease in the expression of PI3K and Raf kinases, whereas an increase in the level of Beclin 1 was observed in the case of autophagy. Inhibition of the expression of this protein by specific siRNA eliminated autophagy. Moreover, the blocking of the expression of Bcl-2 and PI3K significantly increased the level of apoptosis. Osthole and sorafenib successfully inhibited the migration of the MOGGCCM and T98G cells.

The protective effect of herniarin on genotoxicity and apoptosis induced by cisplatin in bone marrow cells of rats

Herniarin is a member of simple coumarins, which are a group of common secondary metabolites in plants. The aim of the present study was to investigate the effects of herniarin on genotoxicity and apoptosis induced by cisplatin in rat bone marrow cells. The experimental rats were treated with four different doses of herniarin (50, 100, 200, and 400 mg/kg.) for seven consecutive days. The cisplatin (5 mg/kg, i.p.) was injected into mice 1 h after the last oral herniarin administration on the seventh day. The protective effects of herniarin were investigated by hematological test, flow cytometry, micronucleus assay, and reactive oxygen species (ROS) level analysis. Herniarin caused a marked reduction in the frequencies of micronucleated polychromatic erythrocytes (MnPCEs) and micronucleated normochromatic erythrocytes (MnNCEs) 24 h after exposure to cisplatin at doses of 200 and 400 mg/kg. Furthermore, herniarin significantly increased the levels of both red and white blood cells in peripheral blood. Treatment of rats with herniarin before cisplatin, significantly decreased the percentage of apoptotic and necrotic cells and the ROS level in bone marrow cells. This study indicated that herniarin can be introduced as a new chemoprotective agent against cisplatin-induced genotoxicity in the future.

Comparative analysis and chemical profiling of different forms of Peucedani Radix

Peucedani Radix, derived from roots of Peucedanum praeruptorum Dunn, is a well-known herb used for centuries in traditional Chinese medicine, which is rich in various coumarins. Four different forms including “earthworm head”, “bamboo-like”, taproots and multi-branched roots have occurred in current producing areas, but the differences in their external features and chemistry have not been concerned till now. In this study, the morphological and microscopic characters of “earthworm head” and “bamboo-like” roots were compared in detail, and qualitative and quantitative characterization of main active coumarins in different forms of Peucedani Radix have been developed by UPCL-Q/TOF-MS and HPLC-DAD, respectively. The results showed that both “earthworm head” and “bamboo-like” consisted of rhizome and root, exhibiting distinct features from normal taproots. Moreover, 53 coumarins including simple coumarins, furanocoumarins and pyranocoumarins were identified or putatively characterized from the four forms samples under the established UPLC-Q/TOF-MS conditions. In addition, the developed quantitative method was successfully applied to simultaneously determine eight main coumarins in 24 batches of four forms Peucedani Radix and 12 batches of dissected “earthworm head” and “bamboo-like” samples. The quantitative results proved that wild “earthworm head” showed higher content of active coumarins and the “bamboo-like” was a rich source of coumarins in cultivated samples, especially for furanocoumarins. These findings would provide reasonable basis for further quality evaluation, grades classification and comprehensive utilization of P. praeruptorum resources.

Application of selective polymeric sorbents for simple coumarins extraction from deodorant samples

Abstract Coumarins (2H-1-benzopyran-2-coumarin derivatives) are derivatives of cinnamic acid naturally occurring in many plants, fungi, and fruits. They are used as ingredients in cosmetics to enhance the aroma and other biological effects. In this work, cosmetic samples (deodorants) were treated by solid phase extraction prior to high performance liquid chromatography determination of coumarins. Traditional sorbent (C18) and selective polymer-based sorbents (laboratory prepared and commercial) were used for solid phase extraction. Recovery values were above 85 % (RSDs below 6 %) except for esculin, where the recovery was lower. Core-shell column of C18 type and gradient of mobile phase methanol—1 % acetic acid were used for high performance liquid chromatography analysis of extracts. Limits of quantitation were 0.5 µg mL−1 for coumarin (ultraviolet detection) and below 12 ng mL−1 for esculin, umbelliferonene, scoparone, 4-methylumbelliferone, herniarin (fluorescence detection). In the tested samples, no coumarins were detected.

Coumarins from Magydaris pastinacea as inhibitors of the tumour-associated carbonic anhydrases IX and XII: isolation, biological studies and in silico evaluation

In an in vitro screening for human carbonic anhydrase (hCA) inhibiting agents from higher plants, the petroleum ether and ethyl acetate extracts of Magydaris pastinacea seeds selectively inhibited hCA IX and hCA XII isoforms. The phytochemical investigation of the extracts led to the isolation of ten linear furocoumarins (1–10), four simple coumarins (12–15) and a new angular dihydrofurocoumarin (11). The structures of the isolated compounds were elucidated based on 1 D and 2 D NMR, MS, and ECD data analysis. All isolated compounds were inactive towards the ubiquitous cytosolic isoform hCA I and II (K i > 10,000 nM) while they were significantly active against the tumour-associated isoforms hCA IX and XII. Umbelliprenin was the most potent coumarin inhibiting hCA XII isoform with a K i of 5.7 nM. The cytotoxicity of the most interesting compounds on HeLa cancer cells was also investigated.

Evaluation of antiparasitary, cytotoxic and antioxidant activity and chemical analysis of Tarenaya spinosa (Jacq.) Raf. (Cleomaceae)

Active principles found in plants may aid in antiparasitic treatments, however it is important to evaluate if they do not have cytotoxicity. The leishmanicidal and trypanocidal activities of Tarenaya spinosa were evaluated, as well as the cytotoxic potential of their extracts, as well as the phytochemical and antioxidant profile. The phytochemical profile was described by Nuclear Magnetic Resonance of Hydrogen (1H-NMR) and High Performance Liquid Chromatography (HPLC-DAD). The antiparasitic activity was performed with the promastigote forms of Leishmania spp. and epimastigotes from Trypanosoma cruzi. Cytotoxicity was assessed using NCTC mammalian clone 929 fibroblasts. The antioxidant potential was assessed with the DPPH free radical. The ethanolic extract (EETS) and aqueous (EATS) presented terpenes, steroids, nitrogen compounds, sugars, phenolic compounds (simple phenylpropanoides and coumarins), flavonoids and chacolnas. The polyphenolic profile showed that caffeic acid was the major compound of both extracts. It was observed that the EETS showed a significant antileishmania activity against L. brasiliensis (LC50 81.75 μg/mL) and L. infantum (LC50 141.6 μg/mL), whereas EATS had low antileishmania activity. Against T. cruzi, the extracts presented LC50 > 1000 μg/mL. The extracts of T. spinosa present high antioxidant activity, with EETS having an IC50 of 377.7 μg/mL and EATS IC50 of 445.8 μg/mL. However, EETS was toxic to fibroblasts with an LC50 of 397.9 μg/mL, whereas no cytotoxicity was observed for EATS. Therefore, EATS is a promising source of antioxidant compounds since it does not present cytotoxicity.

Structure activity Relationship Study of Simple Hydroxyl Coumarins as Antioxidant to Scavenge Hydrogen peroxide

Structure activity Relationship Study of Simple Hydroxyl Coumarins as Antioxidant to Scavenge Hydrogen peroxide

The Age of Coumarins in Plant-Microbe Interactions.

Coumarins are a family of plant-derived secondary metabolites that are produced via the phenylpropanoid pathway. In the past decade, coumarins have emerged as iron-mobilizing compounds that are secreted by plant roots and aid in iron uptake from iron-deprived soils. Members of the coumarin family are found in many plant species. Besides their role in iron uptake, coumarins have been extensively studied for their potential to fight infections in both plants and animals. Coumarin activities range from antimicrobial and antiviral to anticoagulant and anticancer. In recent years, studies in the model plant species tobacco and Arabidopsis have significantly increased our understanding of coumarin biosynthesis, accumulation, secretion, chemical modification and their modes of action against plant pathogens. Here, we review current knowledge on coumarins in different plant species. We focus on simple coumarins and provide an overview on their biosynthesis and role in environmental stress responses, with special attention for the recently discovered semiochemical role of coumarins in aboveground and belowground plant–microbe interactions and the assembly of the root microbiome.

Identification of Antibacterial Phenolics in Selected Plant Species from Mexican Cloud Forest by Mass Spectrometry Dereplication.

Fifteen plant species from a protected cloud forest (CF) in Veracruz, Mexico, were screened for their in vitro capacity to inhibit the growth of the phytopathogenic bacteria Chryseobacterium sp., Pseudomonas cichorii, Pectobacterium carotovorum and Pantoea stewartii, causal agents of damage to crops like 'chayote', lettuce, potato and corn. As a result, the bioactivity of Turpinia insignis and Leandra cornoides is reported for the first time against Chryseobacterium sp. and P. cichorii. In addition, 24 and 18 compounds not described for these species were dereplicated by an UPLC/MS-MS method, respectively. The identified compounds included simple phenols, hydroxycinnamic acids, flavonoids and coumarins. The antibacterial assay of 12 of them demonstrated the bacteriostatic effect of vanillin, trans-cinnamic acid, scopoletin and umbelliferone against Chryseobacterium sp. These findings confirm for the first time the value of the CF plants from Veracruz as sources of bioactive natural products with antimicrobial properties against phytopathogenic bacteria.

A Study on Hydrogen Peroxide Scavenging Activity and Ferric Reducing Ability of Simple Coumarins

Coumarin compounds are δ-lactones where α-pyrone ring is fused with benzene ring. Coumarins are widely distributed in the plant kingdom as well as they are very important in synthetic organic chemistry. Coumarins have great interest because of their abundance in nature and diverse pharmacological activities including antibacterial, antiviral, antipyretic, and anticoagulant, antioxidant, anti-inflammatory and anticancer. This study focused on synthesizing different simple Coumarins and studying their antioxidant activity. Four simple Coumarins (Coumarin (C1), 4-hydroxy coumarin (C2), 7-hydroxy coumarin (C3) and 7-hydoxy-4-methyl coumarin (C4)) were synthesized by using standard methods and were characterized by using UV, IR, 1H and 13C NMR spectra. Antioxidant activity of the simple Coumarins was studied by using standard FRAP assay and Hydrogen peroxide assay and expressed as FRAP value (mmol Fe2+/g) and IC50 value (mg/dm-3) respectively. Ascorbic acid was used as standard. All synthesized simple Coumarins showed both antioxidant activities. Hydroxyl Coumarins (C2, C3 and C4) showed higher activities in both cases than C1. Among the hydroxyl Coumarins C3 showed highest hydrogen peroxide scavenging activity and Ferric reducing capacity too. Antioxidant power of the tested simple Coumarins in decreasing order was C3, C2, C4 and C1 in both cases. But the hydrogen peroxide scavenging activity and Ferric reducing capacity of the all synthesized simple Coumarins were lower when compared to standard ascorbic acid.

HPLC separation and determination of dicoumarol and other simple coumarins in sweet clover

AbstractDicoumarol is a mycotoxin, that acts as a blood anticoagulant, is formed during the microbial action of molds and fungi in spoiled hay or silage containing high-coumarin plant. A HPLC-DAD method for determination of coumarins, including dicoumarol, coumarin, and 4-hydroxycoumarin was developed. Methanol and acetic acid were used as mobile phase with gradient elution. The simultaneous separation was performed using C18 type of stationary phase. The recoveries were 88.6 – 92.6 %, 91.8 – 95.0 %, and 89.7 – 94.1 % (evaluated for three concentration levels) for dicoumarol, coumarin, and 4-hydroxycoumarin respectively. The parameters of system suitability (repeatability of retention times and peak areas) were determined for evaluation of the method. The method showed a good linearity in the concentration range 0.7 – 100 μg.mL−1for dicoumarol, 0.05 – 100 μg.mL−1for coumarin and 4-hydroxycoumarin with correlation coefficients higher than 0.9885. Extracts of sweet clover herb, hay, and spoiled hay were subjected to HPLC-DAD analysis. The most abundant compound in sweet clover herb and hay extracts was coumarin. In spoiled sweet clover hay extract the 4-hydroxycoumarin was detected in addition. The formation of 4-hydroxycoumarin was also observed in the synchronous fluorescence spectra recorded at the wavelength difference of 90 nm (difference between emission and excitation wavelength).