Natural Coumarins: Exploring the Pharmacological Complexity and Underlying Molecular Mechanisms

Abstract

Coumarins belong to the benzopyrone family commonly found in many medicinal plants. Natural coumarins demonstrated a wide spectrum of pharmacological activities, including anti-inflammatory, anticoagulant, anticancer, antibacterial, antimalarial, casein kinase-2 (CK2) inhibitory, antifungal, antiviral, Alzheimer's disease inhibition, neuroprotective, anticonvulsant, phytoalexins, ulcerogenic, and antihypertensive. There are very few studies on the bioavailability of coumarins; therefore, further investigations are necessitated to study the bioavailability of different coumarins which already showed good biological activities in previous studies. On the evidence of varied pharmacological properties, the present work presents an overall review of the derivation, availability, and biological capacities of coumarins with further consideration of the essential mode of their therapeutic actions. In conclusion, a wide variety of coumarins are available, and their pharmacological activities are of current interest thanks to their synthetic accessibility and riches in medicinal plants. Coumarins perform the valuable function as therapeutic agents in a range of medical fields.

1. Introduction

Plants synthesize a large collection of natural products called secondary metabolites [1, 2]. Secondary metabolites have important ecological functions, supporting plant protection against microbes and herbivores and participate in the attraction of pollinators etc. Humans use secondary metabolites as a source of drugs, aromatization, flavouring agents, and for a wide spectrum of other use [3]. Natural compound coumarins have been exposed to considerable phytochemical and pharmacological exploration in the last few decades. It is shown that over the last three years, over 400 coumarins have been described in scientific publications [4].

Coumarins are present naturally in a large number of plants, considerably in high concentration in Coumarouna odorata (tonka bean) (Fabaceae/Leguminosae) [5]. It is also present in high content in vanilla grass (Anthoxanthum odoratum) [6], sweet clover (genus Melilotus) [7], cassia cinnamon (Cinnamomum cassia) [8], in extracts of Justicia pectoralis [9], and a large number of cherry blossom trees [10]. Some species from the Apiaceae family (Prangos Lindl., Ferula L., Heracleum L., Pachypleurum Hoff., Conioselinum Fisch., Libanotis L., and Seseli L.) were rich with coumarin contents [11]. Many plants contain different concentrations of coumarin. Tonka beans, liquorice, and cassia cinnamon have a high concentration of natural coumarins. Some cherry blossom strawberries and apricots contain coumarin in smaller quantities. Despite its sweet smell, animals tend to avoid plants that contain coumarins due to their bitter taste [12]. Coumarins are natural bioactive compounds recognized for their anti-inflammatory, anticoagulant, antibacterial, antifungal, antiviral, anticancer, antihypertensive, antituberculous, anticonvulsant, antiadipogenic, and antihyperglycemic pharmacological activities, as well as its antioxidant and neuroprotective actions [13]. Over 1300 coumarins have been identified from plant sources. Tonka beans can contain, on average, 1% to 3% coumarin [14]. Animal studies have shown that these grains can be toxic, even in small amounts, causing serious liver damage in just a few weeks [15].

Coumarins belong to the benzopyrone family commonly found in many medicinal plants (Figure 1). Their structure consists of two six-membered rings with lactone carbonyl groups. Most coumarin compounds are thermally stable and have notable optical activity [16]. The coumarin biosynthesis takes part in involving multiple P450 enzymes [17]. Ortho-hydroxylation is a key point for the biosynthesis of natural coumarins in plants [18].

Naturally occurring coumarins have been reported for their wide pharmacological activities, including antidiabetic [19], antioxidant, anabolic and hepatoprotective activities [19, 20], antifungal, and anti-inflammatory effects [21–23] (Figure 1). Calanolides, a natural coumarin, isolated from the Calophyllum genus have demonstrated strong anti-HIV activity [24] (Figure 2).

Accordance to evidence of varied pharmacological properties, the current paper presents an overall perspective of the derivation, availability, and biological capacities of coumarins with further consideration of the essential mode of their therapeutic actions.

2. Review Methodology

For this updated review, useful data were collected from the scientific databases PubMed, Science Direct, Scopus, Web of Science, and Elsevier, on the molecular mechanisms and pharmacological studies of natural coumarins and their derivatives. The following MeSH terms were used to search for them: “coumarins,” “chemistry,” “structure-activity relationship,” “pharmacology,” “drug therapy,” “humans,” “clinical trials,” “diabetes,” “anti –Inflammatory,” “neuroprotective,” “antibacterial,” “ antifungal,” and “antiviral.” The scientific names of the plants were verified using PlantList (http://www.theplantlist.org/), and the chemical formulas were verified with ChemSpider.

Inclusion criteria are as follows: preclinical pharmacological studies that highlighted the molecular mechanisms of action and signaling pathways and experimental in vitro and in vivo pharmacological studies.

Exclusion criteria are as follows: studies without obvious mechanisms and doses, works that were not written in English, and studies that included homeopathic preparations.

3. Bioavailability of Coumarins

Bioavailability is described as “the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action.” Usually, bioavailability mentions to the absorption of a compound from the gastrointestinal tract following oral administration of a dosage form [25, 26]. Therefore, it is not enough to know the dosage of taken compound(s); the more important issue is how much of that present is bioavailable. However, compound concentrations regularly cannot be determined directly at the site of action. Therefore, many bioavailability examinations concern to determine the concentration of the active compound in the blood or urine. Thus, bioavailability is involved with how fast and how much of a compound appears in the blood after a specific dose is administered.

A pharmacokinetic study was carried out by Ritschel and Hoffmann [27] who have compared between prolonged-release of coumarin containing tablets with intravenous and peroral administration of coumarin solution in humans, where a correlation was established between the percent of drugs released in vitro and the area under the curve (AUC). Xie and colleagues' [28] study showed that coumarin-based prodrug system produced a fourfold growth in oral bioavailability over the parent drug meptazinol in rats. In another kinetic study, Abraham et al. [29] presented that the absorption of coumarin from cinnamon powder is slightly lower than that of isolated coumarin.

In another research, the exchange of chloride anion by coumarin-3-carboxylate in sertraline, an antidepressant drug, enhances the pharmacological activity of the native drug, binding to bovine serum albumin with higher effect and saving the antimicrobial properties of the antidepressant molecule [30]. Newly designed coumarins can be oppressed for suppression of P-gp-mediated efflux to promote bioavailability of paclitaxel and can suppress breast cancer stem cell development which is crucial for planning potent anticancer drugs [31].

There are very few studies on the bioavailability of coumarins; therefore, future pharmacological studies are needed to study the bioavailability of naturally pharmacologically active coumarins.

4. Natural Coumarins and the Link between Chemical Structures and Pharmacological Effects

Coumarin molecules are made of combined benzene and α-pyrone rings and are chemically 2H-1-benzopyran-2-one which involves a large group of phenolic constituents in plants. The term coumarin derives from Coumarona odorata, a South American vegetable from which the molecule was first isolated in the 1820s. Coumarins were originally isolated in Dipteryx odorata Wild (tonka bean) [32].

They have been observed in over 150 various plants which belong to almost 30 diverse families, of which some important ones are Apiaceae, Caprifoliaceae, Clusiaceae, Guttiferae, Nyctaginaceae, Oleaceae, Rutaceae, and Umbelliferae. Naturally occurring coumarins are chiefly grouped into six types. In Figure 1 and Table 1, different types of coumarin are listed with their reported pharmacological activities.

At the end of the 19th century, farmers in North America introduced sweet clover (Melilotus officinalis) to animal feed and soon a hemorrhagic epidemic arose, which later proved to be correlated with the consumption of sweet clover. During the drying of the clover, coumarin undergoes a series of chemical transformations—partly spontaneous and partly mediated by Aspergillus fungi resulting in dicumarol [56]. Dicumarol interferes with the blood clotting process, blocking the synthesis of vitamin K-dependent clotting factors. One of its chemical derivatives, warfarin, is currently used as an oral anticoagulant in the treatment of deep vein thrombosis, prophylaxis of pulmonary embolism, myocardial infarction in patients with atrial fibrillation, or valve prostheses. Another chemical derivative of dicumarol, acenocoumarol, the active ingredient in sintrom drug, has similar therapeutic indications [57].

Scopoletin from the species Viburnum prunifolium and Angelica (essential oil extracted from the roots) has hypotensive and spasmolytic properties—able to inhibit the spastic contraction of smooth gastrointestinal and genitourinary muscle [58]. Khelline and visnagine, two coumarins of the species Ammi visnaga, have spasmolytic action on the smooth muscle of the coronary vessels with an antianginal effect [59]. Umbelliferone, a coumarin present in the grassy aerial parts of Pilosella and the resins of many Umbelliferae species, is used as a sunscreen and has antibiotic properties against brucellosis [60].

Esculetin, a coumarin present in chestnut leaves (Aesculus hippocastanum) due to the aglycone esculetin decreases the permeability of capillaries and increases their resistance, has anti-inflammatory and phlebotonic effects, improving venous tone. The same coumarin, from the flowers of the sweet clover (Melilotus officinalis), demonstrated antiedematous properties in vivo using animal models. Due to these properties, esculetin in combination with flavonoids is recommended as a phlebotonic adjuvant in the treatment and prophylaxis of chronic venous insufficiency [61]. Esculetin has also bacteriostatic and antifungal properties, while dafnoretin and 3-phenylcoumarins have antiviral properties against hepatitis B virus and anti-HIV. Esculetin also inhibits the synthesis of prostaglandins, thromboxanes and leukotrienes, and proinflammatory molecules involved in asthmatic, allergic, and inflammatory reactions [62].

Phytoalexins are plant-derived coumarins with general protective properties to fungal infection, physical injury, chemical damage, or a pathogenic progression. The main function of phytoalexins is to constrain or destroy the attacking agents like bacteria, viruses, and insects. Ayapin (6,7-methylenedioxycoumarin) is phytoalexin which was initially isolated from Eupatorium ayapana, a member of Asteraceae. Later on it was also isolated from several plants such as Artemisia apiacea [63], Helianthus annuus, Pterocaulon polystachyum [64], and Pterocaulon virgatum [65].

In plants, coumarin can be found in both free and glycosidic form, bound in the form of an aglycone to a glucose molecule. The high structural heterogeneity of coumarins justifies the great pharmacological variability with benefits for human health.

5. The Mechanisms behind the Pharmacological Activities of Natural Coumarins

5.1. Anti-Inflammatory Activity

Inflammation starts with five major signs: pain, swelling, redness, heat, and loss of function which ended up in vascular permeability, leukocytes invasion, production of pain, local oedema, and necrosis [66, 67]. Inflammation can be a denotation of multiple diseases like osteoarthritis, Alzheimer, and atherosclerosis [3]. Moreover, many types of cancers are related to chronic inflammation. Therefore, it is important to deal with inflammation before it turns up into a severe disease [68, 69].

Coumarin possessed anti-inflammatory characteristics, and its mechanism of action involves phagocytosis, production of the enzyme, and proteolysis to eradicate protein and oedema fluid from wounded tissue. One of its derivatives imperatorin also reported for its anti-inflammatory property in lipopolysaccharide-stimulated mouse macrophage (RAW264.7) in vitro as well as in carrageenan-induced mouse paw oedema model in vivo. It stops the protein expression of inducible cyclooxygenase-2 and NO synthase in lipopolysaccharide-stimulated RAW264.7 [70], whereas another derivative esculetin showed its anti-inflammatory potential in rat colitis induced by trinitrobenzene sulfonic acid [34, 71] This coumarin was extracted from Bougainvillea spectabilis and Cichorium intybus.

Coumarins possess antioxidant properties that may contribute to their anti-inflammatory effects [72]. The coumarin 1,2-benzopyrone has long been known to be effective in slowly reducing shoulder lymphedema. The underlying mode of action is unclear, but macrophage-induced proteolysis of the oedema proteins may be implicated.

5.2. Anticoagulant Activity

A complex system controls the blood fluidity in the human body [73]. Blood should remain inside the vasculature and also must clot quickly on exposure to injury [74]. Vitamin K is denoted as a blood anticoagulant, and the structure of warfarin is quite similar to this vitamin. Thus, warfarin is regarded as a vitamin K antagonist because of this structural and functional similarity [75].

Initially, warfarin was used as a poison for rat extermination during laboratory experiments; however, for the past 60 years, it was regarded as an anticoagulant. By mechanism, it inhibits the production of vitamin K-dependent coagulation factors (II, VII, IX, and X) in the liver microsomal. Vitamin K possibly induces the vitamin K-dependent coagulation factors (II, VII, IX, and X), N-terminal glutamate remains to form γ-carboxyglutamates. The reduced vitamin K (Vit KH2) contributes to the γ-carboxylation, and warfarin constrains the epoxide reductase to hinder the Vit KH2 development [75] (Figure 2).

5.3. Anticancer Activity

Cancers are characterized by an uncontrolled division of a group of cells, with the ability to invade other tissues in the body, either by a direct growth in those tissues or by the migration of cells to more distant places in the body (metastasis) [76]. In most cases of cancer, no specific cause of the disease can be identified [77]. Risk factors for cancer include exposure to anthropogens, chemicals, eating habits, and lifestyle [78].

In a recent study, coumarin was reported as a protective agent for mucosa and salivary glands in those patients who are undergoing head and neck radiotherapy [79]. Coumarin also can directly deal with cancer as osthole is active in controlling the migration and attack of breast cancer cells by healing the wound or transwell assays. Luciferase and zymography methods have shown that osthole efficiently hinders matrix metalloproteinase-s promoter and enzyme action, which could be one of the reasons that tend the relocation inhibition and attack by osthole [80], whereas esculetin is reported for its antitumor effects [81] and saves cultured primary neurons from N-methyl-D-aspartate toxicity [82].

Fraxin's defensive properties have been observed in the protection of cytotoxicity prompted by hydrogen peroxide in endothelial cells of the human umbilical vein [41]. Maximum of the coumarins grandivittin, agasyllin, aegelinol benzoate, and osthole displayed marginally cytotoxic effect across the A549 lung cancer cell, and they are usually extracted from Ferulago campestris [49].

5.4. Antibacterial Activity

It had been observed that pathogenic resistance against pharmaceutical and natural antimicrobial agents has been increased in recent times [83, 84]. Therefore, new prototype combinations are required to address this condition [85, 86]. In this regard, plant-based natural antimicrobial agents combined with antibiotics had shown a good potential [87, 88] Coumarins had been reported for combating against both Gram-positive and Gram-negative type of bacteria [89]. Long-chain derivatives of coumarin like ammoresinol and ostruthin showed more efficacy against Bacillus megaterium, Micrococcus luteus, Micrococcus lysodeikticus, and Staphylococcus aureus. However, another type of coumarin, i.e., anthogenol (extracted from Aegle marmelos) [90], displays a potent effect against Enterococcus. Moreover, a furanocoumarin compound imperatorin, which is extracted from Angelica dahurica and A. archangelica (Umbelliferae) [91], controls the growth and spread of Shigella dysenteriae [92]. A substantial antibacterial effect against clinically extracted Gram-positive and Gram-negative bacterial strains (such as Staphylococcus aureus, Salmonella typhi, Enterobacter cloacae, and E. aerogenes) was reported in aegelinol and agasyllin.

5.5. Antifungal Activity

An antifungal coumarin derivative, i.e., osthole, was extracted from Angelica pubescens, Cnidium monnieri [93], and Peucedanum ostruthium [94]. It showed a broad range of fungicidal property against microorganisms like Botrytis cinerea, Fusarium graminearum, Phytophthora capsici, Rhizoctonia solani, and Sclerotinia sclerotiorum [36]. After multiple antifungal experimentations, three most efficient have been reported, i.e., psoralen, imperatorin, and ostruthin [17].

5.6. Antiviral Activity

Coumarin is one of the herbal products which possess anti-HIV capabilities [95]. Inophyllums and calanolides (coumarin derivatives) presented new HIV inhibitory potential. Inophyllums A, B, C, E, P, G1, and G2 were extracted from Achatina fulica. Inophyllums B and P are reported to stop the activity of HIV reverse transcriptase with IC₅₀ values of 38 and 130 nM, respectively. Moreover, both were also found effective against HIV-1 in cell culture (IC₅₀ of 1.4 and 1.6 μM) [51].

Calanolides A and B were extracted from the foliar parts of Calophyllum lanigerum. Studies reported both calanolides A and B as totally protective against replication of HIV-1 [52]. The (+)-calanolide A is a nonnucleoside reverse transcriptase suppressant with the potential efficacy against HIV-1. However, (−)-calanolide B and (−)-dihydrocalanolide B showed antiviral activities comparable to (+)-calanolide A [53, 96]. Formerly inophyllum A and (−)-calanolide B were derived from the seed oil of Calophyllum inophyllum Linn and C. cerasiferum Vesque, correspondingly. Both of them are members of the family Clusiaceae and known for effective HIV-1 reverse transcriptase blockers [97]. Pyranocoumarins (pseudocordatolide C and calanolide F) were extracted from Calophyllum lanigerum var. austrocoriaceum and C. teysmannii var. inophylloide (King) P. F. Stevens (Clusiaceae). Both of these compounds demonstrated anti-HIV effect properties [54], whereas imperatorin also reported inhibiting both vesicular stomatitis and gp160-enveloped recombinant HIV-1 infection in numerous T-cell and HeLa cell lines [98].

Coumarin-linked benzoxazole-5-carboxylic acids showed the inhibitory activity against hepatitis virus RNA polymerase. Inhibiting effect against hepatitis virus RNA polymerase can be demonstrated by coumarin-linked benzoxazole-5-carboxylic acids. Currently, it has been discovered that benzoxazole is conjugated with a coumarin with this methylene linker which displayed strong inhibitory activities on the hepatitis virus [99].

The coumarins have been found to exert antiviral activities including an interesting potential activity against the hepatitis C virus [100]. Likewise, different coumarins such as novobiocin and its analogues have shown antimicrobial activity. Novobiocin, extracted from Streptomyces niveus, is principally effective against Gram-positive bacteria. This drug is little used, however, due to the high incidence of associated adverse reactions and the frequent appearance of resistant strains.

5.7. Neuroprotective Effect

Neurodegenerative diseases are characterized by progressive dysfunction and neuronal loss, due in most cases to the accumulation of proteins with altered physicochemical properties [101]. This process causes the death of neurons in which it accumulates and the alteration of neural connections, influencing movement, speech, memory, intelligence, and other brain functions, following the areas where changes occur in the central nervous system [102].

Alzheimer disease is the degenerative disorder of the CNS (central nervous system) which is distinguished by weakening in memory, intellectual poor operation, personality alteration, and language obstruction [103, 104]. The prevalence of this disease is increasing day by day, and it is most common in old aged people [105]. Researches in recent times showed that coumarin and its derivatives can inhibit this disease [106].

A researcher group of Matos synthesized a sequence of 3-substituted coumarin derivatives, which work as an active inhibitor of monoamine oxidase A and B (MAO-A and MAO-B) isoforms and acetylcholinesterase (AChE) [107].

Esculetin showed neuroprotective action on cerebral ischemia damage in a middle cerebral artery-blocking model in mice at 20 μg/mL [108].

Coriandrum sativum (coriander) is an essential medicinal plant containing coumarin as an effective component with neuroprotective effects that improve memory. A series of coumarin 7-substituted derivatives have been developed to demonstrate the inhibitory properties of choline esterase and monoamine oxidase B (MAO-B) [109]. In this regard, it has been reported that various coumarin derivatives selectively inhibit the enzyme MAO-B, implicated in Alzheimer's disease, and prevent Aβ1-42 aggregation, with low toxicity in the studied cells lines. These results suggest possible applications in the management of Alzheimer's disease.

5.8. Antidiabetic Properties

There is a clear association between diabetes mellitus and cardiovascular complications, and in this regard, the coumarins would be even more valuable if they were found to be effective against diabetes. In theory, these drugs would not only lower blood glucose but also improve the outcomes in terms of the cardiovascular complications of diabetic patients. In this regard, different studies have found plant extracts containing coumarins to exhibit antidiabetic activity [110]. Osthole containing volatile oil from roots of Prangos pabularia significantly inhibited protein tyrosine phosphatase 1B (PTP-1B) with an IC₅₀ value of 0.06 ± 0.01 μg/mL [37].

6. Coumarins in Clinical Trials

6.1. Role of Coumarin in Cardiovascular Diseases

On reviewing the ClinicalTrials.gov database, we found only 7 clinical studies registered using the keywords “coumarin” or “coumarins” (Table 2). However, on adding the term “antivitamin K,” we identified 10 publications, and the addition of “warfarin” yielded 375 registered studies.

In the last few years, modern direct oral anticoagulants (DOACs) have been generated. Instead of acting upon some factors within the coagulation cascade (like the VKAs), these drugs are targeted to a specific component of the cascade. Furthermore, DOACs show scant interaction with other medications or foods and can be administered at fixed doses without having to monitor the patient coagulation status. This allows simplification of long-term anticoagulation therapy [111].

Randomized studies have evaluated the role of oral anticoagulation with VKAs in the primary prevention of thromboembolic events in patients with nonvalvular atrial fibrillation [112–118]. One of the first of these studies was the Copenhagen AFASAK trial [113], which showed the superiority of anticoagulation with VKAs as thromboembolic prophylaxis among patients with atrial fibrillation. The research found warfarin to be more effective than aspirin or placebo in this context, with an annual stroke incidence of 2.0% (95% confidence interval [95% CI] 0.6-4.8) in the warfarin group versus 5.5% (95% CI 2.9-9.4) in the aspirin and placebo groups. The drug also reduced overall vascular mortality.

The results of the SPAF trial became known one year later [112]. This was a work involving a larger sample size and a follow-up period of 16 months. It recorded thromboembolic episodes, bleeding, and mortality and reported an annual incidence of thromboembolic events of 2.3% in the warfarin group versus 7.4% in the placebo group (relative risk [RR] = 0.67 in favour of warfarin [95% CI 0.27-0.85]; p = 0.01). In turn, the bleeding risk was 1.2% annually in the warfarin group and proved much lower than in the Copenhagen AFASAK trial [113], probably because of the use of less intense anticoagulation (INR 2.0-4.5). Likewise, in 1991, the CAFA (Canadian Atrial Fibrillation Anticoagulation) trial [115] compared warfarin (INR 2-3) in 187 patients versus placebo in 191 patients, with a follow-up of 16 months. The study endpoints were thromboembolic events and bleeding, and here again, the findings favoured warfarin both in terms of the number of such events and the incidence of bleeding.

Lastly, in 1992 ,the SPINAF (Stroke Prevention in Nonrheumatic Atrial Fibrillation) examination [116] contrasted low-dose warfarin (INR 1.4-2.8) versus placebo. A total of 571 males (525 in the context of primary prevention and 46 with previous CVA) were distributed to either warfarin (n = 281) or placebo (n = 290), with a follow-up period of 22-month years. The study endpoints were thromboembolic events, bleeding, and mortality. Besides the patients with no history of CVA, 19 of those administered placebos suffered thromboembolic events (annual rate 4.3%) versus only four of those administered warfarin (annual rate 0.9%) (RR = 0.79 in favour of warfarin [95% CI 0.52-0.90]; p = 0.001)—this observation causing early termination of the trial.

In 2016, Cannon et al. (ClinicalTrials.gov NCT 02164864) [111] studied a series of patients with atrial fibrillation subjected to coronary stent placement and anticoagulation for the prevention of CVA and stent thrombosis. The patients with atrial fibrillation subjected to stent placement were seen to have a lesser risk of bleeding when dual therapy was provided in the form of dabigatran and a P2Y12 inhibitor than when triple therapy was administered with warfarin, a P2Y12 inhibitor, and aspirin. Dual healing was not inferior to the triple-drug strategy in terms of thromboembolic risk.

About deep venous thrombosis, the EINSTEIN-DVT trial (ClinicalTrials.gov NCT00440193) [119] was an open-label study in which patients were randomized to rivaroxaban or enoxaparin, followed by a VKA agent that could be warfarin or acenocoumarol, during 3, 6, or 12 months. The sufficiency results were found to be independent of the type of VKA administered, thus suggesting that the efficacy of the two VKAs may be similar.

The coagulation system plays a crucial role in tumor development and metastasis. This has led to increasing interest in the potential benefits of anticoagulation in this field. Concerning cancer patients, several researchers [120–122] have reported a substantial risk of recurrent thrombosis in such individuals despite oral anticoagulation therapy. On comparing low molecular weight heparin (LMWH) versus coumarin, dalteparin was seen to be more active than an oral anticoagulant in risk reduction of recurrent thromboembolism, apart from incrementing bleeding risk.

Ntaios et al. [123] conducted a meta-analysis of 28 observational surveys matching the application of DOACs versus VKAs in patients with atrial fibrillation. All of the evaluated DOACs were supported to a clear and marked decrease in intracranial haemorrhage. In the latest research published by Esteve-Pastor et al. [124], non-VKA anticoagulants have been proposed as an alternative for patients with atrial fibrillation. Direct oral anticoagulants are an interesting therapeutic option, but further investigations are required before their widespread use can be recommended.

6.2. Studies on the Efficacy of Coumarins in Cancer Patients

Grotz et al. [125] studied the validity of combination coumarin/troxerutin therapy in protecting the salivary glands and mucous membranes of patients subjected to head and neck radiotherapy. In turn, Thornes et al. reported the efficacy of coumarin (warfarin) as adjuvant therapy in melanoma [126, 127] (Table 3).

The antitumor effect of coumarin in patients with renal cell carcinoma has been studied by administering the drug at an oral dose of 100 mg/day with the addition of cimetidine (four 300 mg doses a day from day 15 of treatment), with interesting results and practically no side effects [128, 129].

Concerning prostate cancer, patients have been treated with coumarin (3 g/day), and although the results indicated partial tumor response, the tumor burden was seen to decrease in all cases [130].

Warfarin has proved notably positive achievements in the handling of small-cell lung carcinoma. Mousa [131] found that anticoagulation with typically used drugs like nonfractionated heparin and warfarin (Coumadin®) prevents cancer development by limiting tumor cell capacity. The recent finding indicates that anticoagulant drugs and treatment with cimetidine in malignant disease can enhance patient survival and inhibit metastatic action [131].

Zacharski et al., in a phase III trial (study 75), evaluated patients with small cell and non-small-cell lung carcinoma, colon cancer, head and neck malignancies, and pancreatic cancer. The patients received chemotherapy together with warfarin or chemotherapy alone. The authors found warfarin to be associated with improved survival among the patients with small-cell lung carcinoma subjected to chemotherapy versus the patients with non-small-cell lung carcinoma (p = 0.018). No considerable variation was noted in the rest of the malignancies [132–134]. A randomized, prospective study of advanced small-cell lung carcinoma reported benefits in terms of tumor response and survival, though at the cost of more frequent bleeding [135]. A Norwegian population study published in JAMA Internal Medicine [136] provided data on the influence of warfarin on cancer risk. Among the subjects administered warfarin, 9.4% were diagnosed with cancer, versus 10.6% of the population not treated with warfarin. This lesser presence of malignancy in the warfarin group was particularly manifested in patients with lung cancer and atrial fibrillation, where the incidence was lower than among the rest (incidence rate ratio [IRR]: 0.39). However, in the case of colon cancer, warfarin showed no effects in terms of incidence in this population.

Lastly, a recent Cochrane review (2017) on the effects of oral VKAs in cancer patients [137] has concluded that these drugs offer no benefits in terms of survival in patients not diagnosed with thrombosis (i.e., without anticoagulation indications). Concerning the antitumor potential of VKAs (warfarin), the high associated bleeding rates have limited their use in this field. Furthermore, the negative data of the Cochrane review and the great variability of the blood levels of these drugs when administered with cytostatic agents indicate that they afford suboptimal therapeutic outcomes.

Further clinical trials are needed, with patient groups that are homogeneous in terms of the variety of cancer involved, the phase of the disease, and lifetime.

7. Discussion

The pharmacological activities and therapeutic applications of the simple coumarins are dependent upon their chemical substitution profile [23]. Anticancer drugs are designed to defect the abnormally dividing cell by disturbing the cell division action [142, 143]. Chemicals like DNA intercalating and cross-linking agents, topoisomerase inhibitors, cytoskeleton disrupting agents, and antimetabolites are in practice as anticancer drugs [144]. However, apart from the effectiveness of these drugs, multiple side effects have been seen (e.g., haematopoietic system). Occasionally, collective therapies are more preferably used to treat the disease which allows the least side effects during treatment. At present, surgery, chemotherapy, and radiotherapy in combination offer the best treatment for patients. Coumarin is not only effective in cancer treatment but also helps to reduce undesirable outcomes resulted in radiotherapy [65, 145].

High doses of bergapten, a coumarin found in bergamot and citrus essential oil in general, are mutagenic and carcinogenic [146]; in addition, they appear to be responsible for the inhibitory activity of the CYP3A4 isoform of cytochrome P450, characteristic of grapefruit juice (which therefore reduces the metabolism of many drugs, increasing therapeutic activity with the risk of adverse reactions from overdose) [146].

Other studies have shown that coumarin lowers glutamate levels in the hippocampus and stimulates the release of endogenous amino acids such as glutamate, taurine, and glycine in the prefrontal cortex, thus justifying the efficacy of coumarin in the treatment of neurodegenerative diseases, which are directly correlated with central nervous system imbalance. Due to its inhibitory effect on MAO, coumarins may have antidepressant properties.

Although in this updated review, some potential therapeutic effects beneficial to human health have been highlighted; there are still some limitations and clinical pitfalls that must be considered before recommending them as complementary/adjuvant treatments.

Coumarin chromen-2-one is a poisonous chemical compound found in many plants such as cinnamon, mint, green tea, and lavender [147]. In addition, this compound is the precursor of several anticoagulant drugs such as warfarin.

Coumarin derivatives such as warfarin and acenocoumarol, both of which are vitamin K antagonists (VKAs)—are widely prescribed throughout the world as oral anticoagulants to prevent and treat thromboembolic disorders. The efficacy and safety of acenocoumarol have been evaluated in atrial fibrillation, deep venous thrombosis (DVT), and heart valve replacement surgery, following acute myocardial infarction, in the postoperative period of major surgery and also in cases of prolonged hospital stay. Acenocoumarol is effective and safe in all age groups. In comparison with warfarin, it affords greater stability of the anticoagulant effect. However, treatment with coumarin derivatives remains a challenge, since the response to a given dose is characterized by great inter- and intraindividual variability. This is because certain CYP2C9 and VKORC1 polymorphisms are related to lesser dose prescription and greater bleeding risk. Acenocoumarol is inexpensive and may be an adequate oral coagulant for prolonged use. The VKAs are well tolerated and have an excellent cost-efficacy ratio. Moreover, the experience gained with the use of these drugs is very extensive, and the anticoagulation control afforded in the real-life setting is reasonable (with excellent control in the presence of patient self-control). On the other hand, the VKAs have a universally available antidote (vitamin K) that is very easy to use and inexpensive. In general, VKAs pose a slightly increased risk of intracranial haemorrhage, though a probably lesser risk of gastrointestinal bleeding compared with other drugs [148–151]. Optimum anticoagulation should seek a proportion among the prohibition of cerebrovascular accidents (CVAs) and the appearance of bleeding complications. In this respect, standardized VKA therapy based on an international normalized ratio (INR) of 2-3 is effective.

On the other hand, VKAs have well-known limitations, including a narrow therapeutic window, easy access and disappearance of effect, numerous pharmacological and food interactions, unpredictable pharmacokinetics (great inter- and intraindividual variability in response to a given drug dose, as commented above), and the need for periodic laboratory test monitoring with frequent dose adjustments that complicate treatment and interfere with patient quality of life [23, 148–151].

Natural coumarins have also a casein kinase-2 (CK2) inhibitory activity. CK2 is perhaps the best-known pleiotropic protein kinases which have greater than the three hundred recognizable protein substrate, and this could be the probable reason for its fermentative action. The two enzymatic subunits are effective in either presence or absence of regulatory subunits. However, the active CK2 is universal, crucial, and associated in a diverse range of imperative cell functions, but evidence suggested that its enzymatic subunits can also act as oncogenes. It is observed that they show an antiapoptotic influence in prostatic carcinoma cell lines. Coumarin-linked piperazine is considered the most promising inhibitor of CK2 [152]. The experiment showed that this inhibitor crystalized in complex with CK2, and the trial binding mode has been used to derive the linear interaction energy (LIE) model. In the past several years, multiple testing programs have been done by employing both in silico and conventional methods to discover novel powerful and electively CK2 blocking agents.

Particular attention should be paid to the use of dried plants containing coumarin, due to the already mentioned capacity to produce dicumarol in certain situations. These natural compounds are contraindicated in patients undergoing treatment with coumarin anticoagulants such as sintrom or antiplatelet agents (aspirin and clopidogrel).

Although the existing clinical trials are limited, their findings suggest a positive impact of anticoagulation in cancer patients. Nevertheless, this advantage is not the same in all cases, since some histological types of tumor appear to be extra responsive to the action of anticoagulation therapy than others in the early stages of neoplastic development [120–122].

Due to their photosensitizing properties, 6, 7-furano-coumarins are contraindicated in case of prolonged exposure to sunlight, due to the risk of photodermatitis, burns, and melanomas [153]. Doses of coumarin in a human's daily diet were calculated at 0.02 mg/bw, and the concentration of coumarin varies from 1 m/bw in celery to 7000 mg/bw in Ceylon cinnamon and over 87000 mg/bw in Cassia cinnamon. Therefore, the association of nutritional supplements containing coumarins with these plants should be avoided [14]. Due to the proven hepatotoxicity in experimental studies in rats, FDA has banned the use of coumarin as a food additive [154]. However, adverse events in humans after natural coumarin administration were rare.

8. Concluding Remarks and Perspectives

Coumarins belong to the benzopyrone family widespread in nature. Natural coumarins demonstrated a wide spectrum of pharmacological activities, including anti-inflammatory, anticoagulant, anticancer, antibacterial, antimalarial, casein kinase-2 (CK2) inhibitory, antifungal, antiviral, Alzheimer's disease inhibition, neuroprotective, anticonvulsant, phytoalexins, ulcerogenic, and antihypertensive. There are very few studies on the bioavailability of coumarins; therefore, extra investigations are required to study the bioavailability of different coumarins which already showed good biological activities in previous studies.

Based on the wide range of pharmacological effects, this review presents a common analysis of the origin, availability, and biological capacities of coumarins with a further discussion on the most crucial mode of their therapeutic actions. The coumarins play an important task in different pharmacological pathways and make a significant contribution to the development of new therapeutic targets. In conclusion, a broad variety of coumarins are available, and their pharmacological activities are of current interest thanks to their synthetic accessibility and richness in plants and other natural objects. Coumarins play an essential role as therapeutic agents in a range of medical fields.

References

1. Salehi B., Quispe C., Chamkhi I.. Pharmacological properties of chalcones: a review of preclinical including molecular mechanisms and clinical evidence. Frontiers in Pharmacology. 2021 doi:10.3389/fphar.2020.592654 PubMed
2. Erb M., Kliebenstein D. J.. Plant secondary metabolites as defenses, regulators, and primary metabolites: the blurred functional trichotomy. Plant Physiology. 2020 doi:10.1104/pp.20.00433 PubMed
3. Salehi B., Rescigno A., Dettori T.. Avocado-soybean unsaponifiables: a panoply of potentialities to be exploited. Biomolecules. 2020 doi:10.3390/biom10010130 PubMed
4. Sarker S. D., Nahar L.. Progress in the chemistry of naturally occurring coumarins. Progress in the Chemistry of Organic Natural Products. 2017 doi:10.1007/978-3-319-59542-9_3 PubMed
5. Borges M. F., Roleira F. M., Milhazes N. J., Villare E. U., Penin L. S.. Simple coumarins: privileged scaffolds in medicinal chemistry. Frontiers in Medicinal Chemistry. 2009
6. Tava A.. Coumarin-containing grass: volatiles from sweet vernalgrass (Anthoxanthum odoratum L.). Journal of Essential Oil Research. 2001 doi:10.1080/10412905.2001.9712236
7. Luo K., Jahufer M. Z., Wu F.. Genotypic variation in a breeding population of yellow sweet clover (Melilotus officinalis). Frontiers in Plant Science. 2016 doi:10.3389/fpls.2016.00972 PubMed
8. Blahová J., Svobodová Z.. Assessment of coumarin levels in ground cinnamon available in the Czech retail market. The Scientific World Journal. 2012 doi:10.1100/2012/263851 PubMed
9. Leal L. K., Ferreira A. A., Bezerra G. A., Matos F. J., Viana G. S.. Antinociceptive, anti-inflammatory and bronchodilator activities of Brazilian medicinal plants containing coumarin: a comparative study. Journal of Ethnopharmacology. 2000 doi:10.1016/S0378-8741(99)00165-8 PubMed
10. Poonam V., Raunak G. K., Reddy C. S. L.. Chemical constituents of the genus Prunus and their medicinal properties. Current Medicinal Chemistry. 2011 doi:10.2174/092986711803414386 PubMed
11. Sharopov F., Setzer W. N., Egamberdieva D., Öztürk M.. Medicinal plants of Tajikistan. Vegetation of Central Asia and environs. 2018
12. Menezes J. C. J. M. D. S., Diederich M. F.. Natural dimers of coumarin, chalcones, and resveratrol and the link between structure and pharmacology. European Journal of Medicinal Chemistry. 2019 doi:10.1016/j.ejmech.2019.111637 PubMed
13. Al-Warhi T., Sabt A., Elkaeed E. B., Eldehna W. M.. Recent advancements of coumarin-based anticancer agents: an up-to-date review. Bioorganic Chemistry. 2020 doi:10.1016/j.bioorg.2020.104163 PubMed
14. Garg S. S., Gupta J., Sharma S., Sahu D.. An insight into the therapeutic applications of coumarin compounds and their mechanisms of action. European Journal of Pharmaceutical Sciences. 2020 doi:10.1016/j.ejps.2020.105424 PubMed
15. Ma X., Jiang Y., Wen J., Zhao Y., Zeng J., Guo Y.. A comprehensive review of natural products to fight liver fibrosis: alkaloids, terpenoids, glycosides, coumarins and other compounds. European Journal of Pharmacology. 2020 doi:10.1016/j.ejphar.2020.173578 PubMed
16. Kadhum A. A., Al-Amiery A. A., Musa A. Y., Mohamad A. B.. The antioxidant activity of new coumarin derivatives. International Journal of Molecular Sciences. 2011 doi:10.3390/ijms12095747 PubMed
17. Bourgaud F., Hehn A., Larbat R.. Biosynthesis of coumarins in plants: a major pathway still to be unravelled for cytochrome P450 enzymes. Phytochemistry Reviews. 2006 doi:10.1007/s11101-006-9040-2
18. Shimizu B.. 2-Oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins. Frontiers in Plant Science. 2014 doi:10.3389/fpls.2014.00549 PubMed
19. Sharma R., Arya V.. Review on fruits having anti-diabetic potential. Journal of Chemical and Pharmaceutical Research. 2011
20. Bubols G. B., Vianna Dda R., Medina-Remon A.. The antioxidant activity of coumarins and flavonoids. Mini Reviews in Medicinal Chemistry. 2013 doi:10.2174/138955713804999775 PubMed
21. Torres R., Faini F., Modak B., Urbina F., Labbé C., Guerrero J.. Antioxidant activity of coumarins and flavonols from the resinous exudate of Haplopappus multifolius. Phytochemistry. 2006 doi:10.1016/j.phytochem.2006.03.016 PubMed
22. Al-Amiery A. A., Kadhum A. A. H., Mohamad A. A.. Antifungal activities of new coumarins. Molecules. 2012 doi:10.3390/molecules17055713 PubMed
23. Kirsch G., Abdelwahab A. B., Chaimbault P.. Natural and synthetic coumarins with effects on inflammation. Molecules. 2016 doi:10.3390/molecules21101322 PubMed
24. Kostova I.. Synthetic and natural coumarins as cytotoxic agents. Current Medicinal Chemistry-Anti-Cancer Agents. 2005 doi:10.2174/1568011053352550 PubMed
25. Chow S. C.. Bioavailability and bioequivalence in drug development. Wiley Interdisciplinary Reviews: Computational Statistics. 2014 doi:10.1002/wics.1310 PubMed
26. Dalton J. T., Yates C. R., Swarbrick J.. Bioavailability of Drugs and Bioequivalence. Encyclopedia of pharmaceutical technology. 2007
27. Ritschel W. A., Hoffmann K. A.. Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form. Journal of Clinical Pharmacology. 1981 doi:10.1002/j.1552-4604.1981.tb01770.x PubMed
28. Xie Q., Wang X., Wang X., Jiang Z., Qiu Z.. Design, synthesis, and bioavailability evaluation of coumarin-based prodrug of meptazinol. Bioorganic & Medicinal Chemistry Letters. 2005 doi:10.1016/j.bmcl.2005.08.016 PubMed
29. Abraham K., Pfister M., Wöhrlin F., Lampen A.. Relative bioavailability of coumarin from cinnamon and cinnamon-containing foods compared to isolated coumarin: a four-way crossover study in human volunteers. Molecular Nutrition & Food Research. 2011 doi:10.1002/mnfr.201000394 PubMed
30. Escudero G. E., Laino C. H., Echeverría G. A.. Improving the antidepressant action and the bioavailability of sertraline by co-crystallization with coumarin 3-carboxylate. Structural determination. Chemico-biological interactions. 2016 doi:10.1016/j.cbi.2016.03.010 PubMed
31. Tripathi A., Misra K.. Inhibition of P-glycoprotein mediated efflux of paclitaxel by coumarin derivatives in cancer stem cells: an in silico approach. Combinatorial Chemistry & High Throughput Screening. 2016 doi:10.2174/1386207319666160517115158 PubMed
32. Lončar M., Jakovljević M., Šubarić D.. Coumarins in food and methods of their determination. Food. 2020 doi:10.3390/foods9050645 PubMed
33. Thomas V., Giles D., Basavarajaswamy G., Das A., Patel A.. Coumarin derivatives as anti-inflammatory and anticancer agents. Anti-Cancer Agents in Medicinal Chemistry. 2017 doi:10.2174/1871520616666160902094739 PubMed
34. Witaicenis A., Seito L. N., Di Stasi L. C.. Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis. Chemico-Biological Interactions. 2010 doi:10.1016/j.cbi.2010.03.045 PubMed
35. Venugopala K. N., Rashmi V., Odhav B.. Review on natural coumarin lead compounds for their pharmacological activity. BioMed Research International. 2013 doi:10.1155/2013/963248 PubMed
36. Wang C. M., Zhou W., Li C. X., Chen H., Shi Z. Q., Fan Y. J.. Efficacy of osthol, a potent coumarin compound, in controlling powdery mildew caused by Sphaerotheca fuliginea. Journal of Asian Natural Products Research. 2009 doi:10.1080/10286020903158964 PubMed
37. Numonov S., Sharopov F. S., Atolikhshoeva S.. Volatile secondary metabolites with potent antidiabetic activity from the roots of Prangos pabularia Lindl.—Computational and experimental investigations. Applied Sciences. 2019 doi:10.3390/app9112362
38. May J. M., Owens T. W., Mandler M. D.. The antibiotic novobiocin binds and activates the ATPase that powers lipopolysaccharide transport. Journal of the American Chemical Society. 2017 doi:10.1021/jacs.7b07736 PubMed
39. Feng D., Zhang A., Yang Y., Yang P.. Coumarin-containing hybrids and their antibacterial activities. Archiv der Pharmazie. 2020 doi:10.1002/ardp.201900380 PubMed
40. Portugal J.. Chartreusin, elsamicin A and related anti-cancer antibiotics. Current Medicinal Chemistry. 2003 doi:10.2174/1568011033482215 PubMed
41. Whang W. K., Park H. S., Ham I.. Natural compounds, fraxin and chemicals structurally related to fraxin protect cells from oxidative stress. Experimental and Molecular Medicine. 2005 doi:10.1038/emm.2005.54 PubMed
42. Chiang C. C., Cheng M. J., Peng C. F., Huang H. Y., Chen I. S.. A novel dimeric coumarin analog and antimycobacterial constituents from Fatoua pilosa. Chemistry and Biodiversity. 2010 doi:10.1002/cbdv.200900326 PubMed
43. Majnooni M. B., Fakhri S., Shokoohinia Y., Mojarrab M., Kazemi-Afrakoti S., Farzaei M. H.. Isofraxidin: synthesis, biosynthesis, isolation, pharmacokinetic and pharmacological properties. Molecules. 2020 doi:10.3390/molecules25092040 PubMed
44. Kuo P. C., Hsu M. Y., Damu A. G.. Flavonoids and coumarins from leaves of Phellodendron chinense. Planta Medica. 2004 doi:10.1055/s-2004-815500 PubMed
45. Shin E., Choi K. M., Yoo H. S., Lee C. K., Hwang B. Y., Lee M. K.. Inhibitory effects of coumarins from the stem barks of Fraxinus rhynchophylla on adipocyte differentiation in 3T3-L1 cells. Biological and Pharmaceutical Bulletin. 2010 doi:10.1248/bpb.33.1610 PubMed
46. Grabarska A., Skalicka-Woźniak K., Kiełbus M.. Imperatorin as a promising chemotherapeutic agent against human larynx cancer and rhabdomyosarcoma cells. Molecules. 2020 doi:10.3390/molecules25092046 PubMed
47. Kharasch E. D., Hankins D. C., Taraday J. K.. Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity. Drug Metabolism and Disposition. 2000 PubMed
48. Chakthong S., Weaaryee P., Puangphet P.. Alkaloid and coumarins from the green fruits of _Aegle marmelos_. Phytochemistry. 2012 doi:10.1016/j.phytochem.2011.11.018 PubMed
49. Rosselli S., Maggio A. M., Faraone N.. The cytotoxic properties of natural coumarins isolated from roots of Ferulago campestris (Apiaceae) and of synthetic ester derivatives of aegelinol. Natural Product Communications. 2009 PubMed
50. Basile A., Sorbo S., Spadaro V.. Antimicrobial and antioxidant activities of coumarins from the roots of Ferulago campestris (Apiaceae). Molecules. 2009 doi:10.3390/molecules14030939 PubMed
51. Patil A. D., Freyer A. J., Eggleston D. S.. The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn. Journal of Medicinal Chemistry. 1993 doi:10.1021/jm00078a001 PubMed
52. Kashman Y., Gustafson K. R., Fuller R. W.. HIV inhibitory natural products. Part 7. The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum. Journal of Medicinal Chemistry. 1992 doi:10.1021/jm00093a004 PubMed
53. Newman R. A., Chen W., Madden T. L.. Pharmaceutical properties of related calanolide compounds with activity against human immunodeficiency virus. Journal of Pharmaceutical Sciences. 1998 doi:10.1021/js980122d PubMed
54. McKee T. C., Fuller R. W., Covington C. D.. New pyranocoumarins isolated from Calophyllum lanigerum and Calophyllum teysmannii. Journal of Natural Products. 1996 doi:10.1021/np9603784 PubMed
55. Timson D. J.. Dicoumarol: a drug which hits at least two very different targets in vitamin K metabolism. Current Drug Targets. 2017 doi:10.2174/1389450116666150722141906 PubMed
56. Ren Q. C., Gao C., Xu Z.. Bis-coumarin derivatives and their biological activities. Current Topics in Medicinal Chemistry. 2018 doi:10.2174/1568026618666180221114515 PubMed
57. Eichinger S.. Reversing vitamin K antagonists: making the old new again. Hematology. American Society of Hematology. Education Program. 2016 doi:10.1182/asheducation-2016.1.605 PubMed
58. Martínez-Pérez E. F., Juárez Z. N., Hernández L. R., Bach H.. Natural antispasmodics: source, stereochemical configuration, and biological activity. BioMed Research International. 2018 doi:10.1155/2018/3819714 PubMed
59. Khalil N., Bishr M., Desouky S., Salama O.. Ammi visnaga L., a potential medicinal plant: a review. Molecules. 2020 doi:10.3390/molecules25020301 PubMed
60. El-Sharkawy E., Selim Y.. Three new coumarin types from aerial parts of Ammi majus L.. and their cytotoxic activity. Zeitschrift fuer Naturforschung, C: Journal of Biosciences. 2018 doi:10.1515/znc-2017-0068 PubMed
61. Hsia C.-W., Lin K. C., Lee T. Y.. Esculetin, a coumarin derivative, prevents thrombosis: inhibitory signaling on PLCγ2-PKC-AKT activation in human platelets. International Journal of Molecular Sciences. 2019 doi:10.3390/ijms20112731 PubMed
62. Liang C., Ju W., Pei S., Tang Y., Xiao Y.. Pharmacological activities and synthesis of esculetin and its derivatives: a mini-review. Molecules. 2017 doi:10.3390/molecules22030387 PubMed
63. Iranshahi M. E., Askari M., Sahebkar A., Hadjipavlou L. D.. Evaluation of antioxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. Daru. 2009
64. Egan D., O'kennedy R., Moran E., Cox D., Prosser E., Thornes R. D.. The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compounds. Drug Metabolism Reviews. 1990 doi:10.3109/03602539008991449 PubMed
65. Marshall M. E., Butler K., Hermansen D.. Structural modification of coumarin for increased anti-coagulation potency. Prostate. 1990 doi:10.1002/pros.2990170203 PubMed
66. Padureanu R., Albu C. V., Mititelu R. R.. Oxidative stress and inflammation interdependence in multiple sclerosis. Journal of Clinical Medicine. 2019 doi:10.3390/jcm8111815 PubMed
67. Rogoveanu O. C., Calina D., Cucu M. G.. Association of cytokine gene polymorphisms with osteoarthritis susceptibility. Experimental and Therapeutic Medicine. 2018 doi:10.3892/etm.2018.6477 PubMed
68. Docea A. O., Calina D., Buga A. M.. The effect of silver nanoparticles on antioxidant/pro-oxidant balance in a murine model. International Journal of Molecular Sciences. 2020 doi:10.3390/ijms21041233 PubMed
69. Scheau C., Caruntu C., Badarau I. A.. Cannabinoids and inflammations of the gut-lung-skin barrier. Journal of Personalized Medicine. 2021 doi:10.3390/jpm11060494 PubMed
70. Huang G. J., Deng J. S., Liao J. C.. Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory activity of imperatorin from Glehnia littoralis. Journal of Agricultural and Food Chemistry. 2012 doi:10.1021/jf204297e PubMed
71. Kwon O. S., Choi J. S., Islam M. N., Kim Y. S., Kim H. P.. Inhibition of 5-lipoxygenase and skin inflammation by the aerial parts of Artemisia capillaris and its constituents. Archives of Pharmacal Research. 2011 doi:10.1007/s12272-011-0919-0 PubMed
72. Borman P.. Lymphedema diagnosis, treatment, and follow-up from the view point of physical medicine and rehabilitation specialists. Turkish journal of physical medicine and rehabilitation. 2018 doi:10.5606/tftrd.2018.3539 PubMed
73. Sharifi-Rad M., Anil Kumar N. V., Zucca P.. Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Frontiers in Physiology. 2020 doi:10.3389/fphys.2020.00694 PubMed
74. Sharifi-Rad J., Quispe C., Shaheen S.. Flavonoids as potential anti-platelet aggregation agents: from biochemistry to health promoting abilities. Critical Reviews in Food Science and Nutrition. 2021 doi:10.1080/10408398.2021.1924612 PubMed
75. Wojciechowski V. V., Calina D., Tsarouhas K.. A guide to acquired vitamin K coagulophathy diagnosis and treatment: the Russian perspective. Daru. 2017 doi:10.1186/s40199-017-0175-z PubMed
76. Buga A. M., Docea A. O., Albu C.. Molecular and cellular stratagem of brain metastases associated with melanoma. Oncology Letters. 2019 doi:10.3892/ol.2019.9933 PubMed
77. Mitrut P., Rodrigo L.. Colorectal cancer and inflammatory bowel disease. Colorectal Cancer - from Pathogenesis to Treatment. 2016
78. Sharifi-Rad J., Rodrigues C. F., Stojanović-Radić Z.. Probiotics: versatile bioactive components in promoting human health. Medicina-Lithuania. 2020 doi:10.3390/medicina56090433 PubMed
79. Mahler J. L., Gomella L. G., Crawford E. D., Glode L. M., Zippe C. D., Fair W. R.. Synthesis of novel coumarin bisindole derivatives & reported as anti-hyperlipidimic activity. Prostate. 1992 doi:10.1002/pros.2990200208 PubMed
80. Yang D., Gu T., Wang T., Tang Q., Ma C.. Effects of osthole on migration and invasion in breast cancer cells. Bioscience, Biotechnology, and Biochemistry. 2010 doi:10.1271/bbb.100110 PubMed
81. Yun E. S., Park S. S., Shin H. C., Choi Y. H., Kim W. J., Moon S. K.. p38 MAPK activation is required for esculetin-induced inhibition of vascular smooth muscle cells proliferation. Toxicology In Vitro. 2011 doi:10.1016/j.tiv.2011.05.001 PubMed
82. Lee C. R., Shin E. J., Kim H. C., Choi Y. S., Shin T., Wie M. B.. Esculetin inhibits N-methyl-D-aspartate neurotoxicity via glutathione preservation in primary cortical cultures. Laboratory Animal Research. 2011 doi:10.5625/lar.2011.27.3.259 PubMed
83. Zlatian O., Balasoiu A. T., Balasoiu M.. Antimicrobial resistance in bacterial pathogens among hospitalised patients with severe invasive infections. Experimental and Therapeutic Medicine. 2018 doi:10.3892/etm.2018.6737 PubMed
84. Călina D. A., Roșu L. U., Roșu A. F.. Etiological diagnosis and pharmacotherapeutic management of parapneumonic pleurisy. Farmácia. 2016
85. Salehi B., Sharifi-Rad J., Capanoglu E.. Cucurbita plants: from farm to industry. Applied Sciences-Basel. 2019
86. Salehi B., Shivaprasad Shetty M., Anil Kumar V. N.. Veronica plants-drifting from farm to traditional healing, food application, and phytopharmacology. Molecules. 2019 doi:10.3390/molecules24132454 PubMed
87. Salehi B., Prakash Mishra A., Nigam M.. Ficus plants: state of the art from a phytochemical, pharmacological, and toxicological perspective. Phytotherapy Research. 2021 doi:10.1002/ptr.6884 PubMed
88. Călina D., Docea A. O., Rosu L.. Antimicrobial resistance development following surgical site infections. Molecular Medicine Reports. 2017 doi:10.3892/mmr.2016.6034 PubMed
89. Reen F. J., Gutiérrez-Barranquero J. A., Parages M. L., O´Gara F.. Coumarin: a novel player in microbial quorum sensing and biofilm formation inhibition. Applied Microbiology and Biotechnology. 2018 doi:10.1007/s00253-018-8787-x PubMed
90. Evans W. C.. Trease and Evans Pharmacognosy. 2009
91. Baek N. I., Ahn E. M., Kim H. Y., Park Y. D.. Furanocoumarins from the root of Angelica dahurica. Archives of Pharmacal Research. 2000 doi:10.1007/BF02976574 PubMed
92. Raja S. B., Murali M. R., Roopa K., Devaraj S. N.. Imperatorin a furocoumarin inhibits periplasmic Cu-Zn SOD of Shigella dysenteriae their by modulates its resistance towards phagocytosis during host pathogen interaction. Biomedicine & Pharmacotherapy. 2011 doi:10.1016/j.biopha.2010.10.010 PubMed
93. Chou S. Y., Hsu C. S., Wang K. T., Wang M. C., Wang C. C.. Antitumor effects of osthol from Cnidium monnieri: an in vitro and in vivo study. Phytotherapy Research. 2007 doi:10.1002/ptr.2044 PubMed
94. Cisowski W., Sawicka U., Mardarowiczb M., Asztemborskac M., Łuczkiewiczd M.. Essential oil from herb and rhizome of Peucedanum ostruthium (L. Koch.) ex DC. Zeitschrift für Naturforschung C. 2001 doi:10.1515/znc-2001-11-1202 PubMed
95. Mishra S., Pandey A., Manvati S.. Coumarin: an emerging antiviral agent. Heliyon. 2020 doi:10.1016/j.heliyon.2020.e03217 PubMed
96. Stout G. H., Stevens K. L.. The structure of costatolide. Journal of Organic Chemistry. 1964 doi:10.1021/jo01035a041
97. Spino C., Dodier M., Sotheeswaran S.. Anti-HIV coumarins from calophyllum seed oil. Bioorganic and Medicinal Chemistry Letters. 1998 doi:10.1016/s0960-894x(98)00628-3 PubMed
98. Sancho R., Márquez N., Gómez-Gonzalo M.. Imperatorin inhibits HIV-1 replication through an Sp1-dependent pathway. The Journal of Biological Chemistry. 2004 doi:10.1074/jbc.M401993200 PubMed
99. Neyts J., Clercq E. D., Singha R.. Structure−Activity relationship of new anti-Hepatitis C virus agents: Heterobicycle−Coumarin conjugates. Journal of medicinal chemistry. 2009 doi:10.1021/jm801240d PubMed
100. Hassan M. Z., Osman H., Ali M. A., Ahsan M. J.. Therapeutic potential of coumarins as antiviral agents. European Journal of Medicinal Chemistry. 2016 doi:10.1016/j.ejmech.2016.07.056 PubMed
101. Islam M. S., Quispe C., Hossain R.. Neuropharmacological effects of quercetin: a literature-based review. Frontiers in Pharmacology. 2021 doi:10.3389/fphar.2021.665031 PubMed
102. Tsatsakis A., Docea A. O., Calina D.. A mechanistic and pathophysiological approach for stroke associated with drugs of abuse. Journal of Clinical Medicine. 2019 doi:10.3390/jcm8091295 PubMed
103. Salehi B., Sharifi-Rad J., Cappellini F.. The therapeutic potential of anthocyanins: current approaches based on their molecular mechanism of action. Frontiers in Pharmacology. 2020 doi:10.3389/fphar.2020.01300 PubMed
104. Salehi B., Sestito S., Rapposelli S.. Epibatidine: a promising natural alkaloid in health. Biomolecules. 2019 doi:10.3390/biom9010006 PubMed
105. Calina D., Buga A. M., Mitroi M.. The treatment of cognitive, behavioural and motor impairments from brain injury and neurodegenerative diseases through cannabinoid system modulation-evidence from in vivo studies. Journal of Clinical Medicine. 2020 doi:10.3390/jcm9082395 PubMed
106. Hu Y. H., Yang J., Zhang Y.. Synthesis and biological evaluation of 3-(4-aminophenyl)-coumarin derivatives as potential anti-Alzheimer's disease agents. Journal of Enzyme Inhibition and Medicinal Chemistry. 2019 doi:10.1080/14756366.2019.1615484 PubMed
107. Matos M. J., Vilar S., Gonzalez-Franco R. M.. Novel (coumarin-3-yl)carbamates as selective MAO-B inhibitors: synthesis, in vitro and in vivo assays, theoretical evaluation of ADME properties and docking study. European Journal of Medicinal Chemistry. 2013 doi:10.1016/j.ejmech.2013.02.009 PubMed
108. Wang C., Pei A., Chen J.. A natural coumarin derivative esculetin offers neuroprotection on cerebral ischemia/reperfusion injury in mice. Journal of Neurochemistry. 2012 doi:10.1111/j.1471-4159.2012.07744.x PubMed
109. Huang M., Xie S. S., Jiang N., Lan J. S., Kong L. Y., Wang X. B.. Multifunctional coumarin derivatives: monoamine oxidase B (MAO-B) inhibition, anti-β-amyloid (Aβ) aggregation and metal chelation properties against Alzheimer’s disease. Bioorganic & Medicinal Chemistry Letters. 2015 doi:10.1016/j.bmcl.2014.12.034 PubMed
110. Li H., Yao Y., Li L.. Coumarins as potential antidiabetic agents. The Journal of Pharmacy and Pharmacology. 2017 doi:10.1111/jphp.12774 PubMed
111. Cannon C. P., Gropper S., Bhatt D. L.. RE-DUAL PCI steering committee and investigators. Design and rationale of the RE-DUAL PCI trial: a prospective, randomized, phase 3b study comparing the safety and efficacy of dual antithrombotic therapy with dabigatran etexilate versus warfarin triple therapy in patients with nonvalvular atrial fibrillation who have undergone percutaneous coronary intervention with stenting. Clinical Cardiology. 2016 doi:10.1002/clc.22572 PubMed
112. Stroke prevention in atrial fibrillation study. Circulation. 1991 doi:10.1161/01.cir.84.2.527 PubMed
113. Petersen P., Boysen G., Godtfredsen J., Andersen E. D., Andersen B.. Placebo controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation, The Copenhagen AFASAK study. Lancet. 1989 doi:10.1016/s0140-6736(89)91200-2 PubMed
114. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The New England Journal of Medicine. 1990 doi:10.1056/NEJM199011293232201 PubMed
115. Connolly S. J., Laupacis A., Gent M., Roberts R. S., Cairns J. A., Joyner C.. Canadian atrial fibrillation anticoagulation (CAFA) study. Journal of the American College of Cardiology. 1991 doi:10.1016/0735-1097(91)90585-W PubMed
116. Ezekowitz M. D., Bridgers S. L., James K. E.. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. The New England Journal of Medicine. 1992 doi:10.1056/NEJM199211123272002 PubMed
117. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993 PubMed
118. Hart R. G., Pearce L. A., Aguilar M. I.. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine. 2007 doi:10.7326/0003-4819-146-12-200706190-00007 PubMed
119. Prins M. H., Lensing A. W., Bauersachs R.. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thrombosis journal. 2013 doi:10.1186/1477-9560-11-21 PubMed
120. Lee A. Y., Levine M. N., Baker R. I.. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. The New England Journal of Medicine. 2003 doi:10.1056/NEJMoa025313 PubMed
121. Woodruff S., Lee A. Y. Y., Carrier M., Feugère G., Abreu P., Heissler J.. Low-molecular-weight-heparin versus a coumarin for the prevention of recurrent venous thromboembolism in high- and low-risk patients with active cancer: a post hoc analysis of the CLOT study. Journal of Thrombosis and Thrombolysis. 2019 doi:10.1007/s11239-019-01833-w PubMed
122. Woodruff S., Feugère G., Abreu P., Heissler J., Ruiz M. T., Jen F.. A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment. Journal of Thrombosis and Thrombolysis. 2016 doi:10.1007/s11239-016-1386-8 PubMed
123. Ntaios G., Papavasileiou V., Makaritsis K., Vemmos K., Michel P., Lip G. Y. H.. Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 2017 doi:10.1161/STROKEAHA.117.017549 PubMed
124. Esteve-Pastor M. A., Rivera-Caravaca J. M., Roldán V.. Estimated absolute effects on efficacy and safety outcomes of using non-vitamin K antagonist oral anticoagulants in 'real-world' atrial fibrillation patients: a comparison with optimally acenocoumarol anticoagulated patients. International journal of cardiology. 2018 doi:10.1016/j.ijcard.2017.11.087 PubMed
125. Grötz K. A., Wüstenberg P., Kohnen R.. Prophylaxis of radiogenic sialadenitis and mucositis by coumarin/troxerutine in patients with head and neck cancer-a prospective, randomized, placebo controlled, double-blind study. The British Journal of Oral & Maxillofacial Surgery. 2001 doi:10.1054/bjom.2000.0459 PubMed
126. Thornes R. D., Daly L., Lynch G.. Treatment with coumarin to prevent or delay recurrence of malignant melanoma. Journal of cancer research and clinical oncology. 1994 doi:10.1007/BF01377122 PubMed
127. Thornes R. D., Lynch G., Sheehan M. W.. Cimetidine and coumarin therapy of melanoma. Lancet. 1982 doi:10.1016/S0140-6736(82)90295-1 PubMed
128. Dexeus F. H., Logothetis C. J., Sella A.. Phase II study of coumarin and cimetidine in patients with metastatic renal-cell carcinoma. Journal of Clinical Oncology. 1990 doi:10.1200/JCO.1990.8.2.325 PubMed
129. Kokron O., Maca S., Gasser G., Schmidt P. R.. Cimetidine and coumarin therapy of renal cell carcinoma. Oncology. 1991 doi:10.1159/000226905 PubMed
130. Marshall M. E., Butler K., Hermansen D.. Treatment of hormone refractory stage-D carcinoma of prostate with coumarin (1, 2- benzopyrone) and cimetidine: a pilot study. Prostate. 1990 doi:10.1002/pros.2990170203 PubMed
131. Mousa S.. Anticoagulants in thrombosis and cancer: the missing link. Expert Review of Anticancer Therapy. 2002 doi:10.1586/14737140.2.2.227 PubMed
132. Zacharski L. R., Henderson W. G., Rickles F. R.. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75. JAMA. 1981 PubMed
133. Zacharski L. R., Henderson W. G., Rickles F. R.. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer. 1984 doi:10.1002/1097-0142(19840515)53:10<2046::aid-cncr2820531007>3.0.co;2-f PubMed
134. Chahinian A. P., Propert K. J., Ware J. H.. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. Journal of Clinical Oncology. 1989 doi:10.1200/JCO.1989.7.8.993 PubMed
135. Silberberg J. M., Zucker S.. Warfarin anticoagulation for small-cell lung cancer: evidence against a cytotoxic or anticoagulant mechanism. Journal of Clinical Oncology. 1990 doi:10.1200/JCO.1990.8.1.182 PubMed
136. Haaland G. S., Falk R. S., Straume O., Lorens J. B.. Association of warfarin use with lower overall cancer incidence among patients older than 50 years. JAMA Internal Medicine. 2017 doi:10.1001/jamainternmed.2017.5512 PubMed
137. Kahale L. A., Hakoum M. B., Tsolakian I. G.. Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database of Systematic Reviews. 2017 doi:10.1002/14651858.CD006466.pub6 PubMed
138. Daly L.. The first international urokinase/warfarin trial in colorectal cancer. Clinical & Experimental Metastasis. 1991 doi:10.1007/BF01831705 PubMed
139. Levine M., Hirsh J., Arnold A.. Double-blind randomized trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994 doi:10.1016/s0140-6736(94)90008-6 PubMed
140. Stanford C. F.. Anticoagulants in the treatment of small cell carcinoma of the bronchus. Thorax. 1979 doi:10.1136/thx.34.1.113 PubMed
141. Maurer L. H., Herndon J. E., Hollis D. R.. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a cancer and leukemia group B study. Journal of Clinical Oncology. 1997 doi:10.1200/JCO.1997.15.11.3378 PubMed
142. Zlatian O. M., Comănescu M. V., Roşu A. F.. Histochemical and immunohistochemical evidence of tumor heterogeneity in colorectal cancer. Romanian Journal of Morphology and Embryology. 2015 PubMed
143. Docea A. O., Mitruţ P., Grigore D., Pirici D., Călina D. C., Gofiţă E.. Immunohistochemical expression of TGF beta (TGF-beta), TGF beta receptor 1 (TGFBR1), and Ki67 in intestinal variant of gastric adenocarcinomas. Romanian Journal of Morphology and Embryology. 2012 PubMed
144. Skok Ž., Zidar N., Kikelj D., Ilaš J.. Dual inhibitors of human DNA topoisomerase II and other cancer-related targets. Journal of Medicinal Chemistry. 2020 doi:10.1021/acs.jmedchem.9b00726 PubMed
145. Agarwal R.. Synthesis & biological screening of some novel. Coumarin derivatives. Biochemical Pharmacology. 2000
146. Assessment report on Citrus bergamia Risso et Poiteau, aetheroleum. 2012
147. Salehi B., Lopez-Jornet P., Pons-Fuster López E.. Plant-derived bioactives in oral mucosal lesions: a key emphasis to curcumin, lycopene, chamomile, aloe vera, green tea and coffee properties. Biomolecules. 2019 doi:10.3390/biom9030106 PubMed
148. Anand S. S., Yusuf S.. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA. 1999 doi:10.1001/jama.282.21.2058 PubMed
149. Witt D. M.. Approaches to optimal dosing of vitamin K antagonists. Seminars in Thrombosis and Hemostasis. 2012 doi:10.1055/s-0032-1324713 PubMed
150. Ufer M.. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clinical Pharmacokinetics. 2005 doi:10.2165/00003088-200544120-00003 PubMed
151. Tagalakis V., Blostein M., Robinson-Cohen C., Kahn S. R.. The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treatment Reviews. 2007 doi:10.1016/j.ctrv.2007.02.004 PubMed
152. Stefanachi A., Leonetti F., Pisani L., Catto M., Carotti A.. Coumarin: a natural, privileged and versatile scaffold for bioactive compounds. Molecules. 2018 doi:10.3390/molecules23020250 PubMed
153. Guillon C., Jan Y. H., Heck D. E.. Phototoxicity of 7-oxycoumarins with keratinocytes in culture. Bioorganic Chemistry. 2019 doi:10.1016/j.bioorg.2019.103014 PubMed
154. Iwata N., Kainuma M., Kobayashi D.. The relation between hepatotoxicity and the total coumarin intake from traditional Japanese medicines containing cinnamon bark. Frontiers in Pharmacology. 2016 doi:10.3389/fphar.2016.00174 PubMed