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.


INTRODUCTION
atural coumarins, specifically those belonging to plants, seem to be driven from phenolic derivatives and typically consisted ofpyrone and phenyl rings bonded together 1 . As secondary metabolites of bacteria, fungi, and plants, over 1300 coumarins have been recognized 2 . The Tonka bean (Dipteryx odorataWild) was the first source of coumarins detected and then were observed in over 150 other species in approximately 30 distinct families 3 . Apiaceae, Caprifoliaceae, Clusiaceae, Guttiferae, Nyctaginaceae, Oleaceae, Rutaceae, and Umbelliferae are some of the more prominent ones 4 . Coumarins are most abundant in the plant's fruits like Bael fruits (Aegle marmelos 5 ) and Tetrapleura tetraptera TAUB 6 , and seeds like Tonka beans 7 , followed by the roots like Ferulago campestris 8 , the leaves like Murraya paniculata 9 , and the latex of the tropical rainforest tree like Calophyllum teysmannii inophylloide 10 , green tea, as well as chicory and other foods 11 .
A number of essential oils, including cassia oil 12 , cinnamon bark oil 13 , and lavender oil 8 , have significant amounts of these coumarins. Changes in the environment and seasons may have an impact on how coumarins appear in different parts of the plant 14 . Coumarins may serve as bacteriostatics, fungistatics, organizers for the growth of plants, as well as maybe wastes, but their exact role is uncertain.
Coumarins occur naturally in a variety of forms due to the variation in the present conjugations and/or substitutions. Interestingly, the majority of biochemical and medicinal investigations on humans focused upon coumarin as well as its fundamental product of metabolism, 7hydroxycoumarin 15 .

Coumarins' categorization
According to the chemical structure of the molecules, natural coumarins can be divided into six major groups, as listed in Table 1 It is used as an antiviral 32 .

Medicinal Potentials of Natural Coumarins
Many naturally occurring coumarins exhibit intriguing biological characteristics, according to accumulating bits of evidence over the past decades. The most important biomedical properties are displayed in Figure 1. In Table 2, the names of the reported examples with their chemical structures are inserted.  (R13), a glycosidic coumarin, seems to be primarily potent towards bacteria that are Gram-positive, and was discovered in Streptomyces chartreusis 40 . However, the compound has not been tested for medicinal use due to its toxicity 36 .
Phellodenol A is subsequently identified and extracted from Phellodendron amurense var. wilsonii leaves 50 .

Anticoagulant Potential of Natural Coumarins
It was discovered that sweet clover contains dicoumarol (R35) 23 , a coumarin-based compound with anticoagulant properties 24 . Coumarins seem to be vitamin K blockers that act as anticoagulants via inhibiting the cyclic inter-conversion of both vitamin K and vitamin K epoxide 51 . As depicted in Figure 2, upon N-termini of VKD proteins, vitamin K could be a cofactor for the posttranslational carboxylation of glutamate residues to the corresponding -carboxyglutamates 52 . The biological effectiveness of the clotting factors-II, -VII, -IX, and -X is -carboxylation dependent. Coumarins have anticoagulant impacts because they block the conversional cycle of vitamin K, causing the liver to create partly carboxylated and decarboxylated proteins of lower pro-coagulant potential 53 . vitamin K antagonists also have the potential to be pro-coagulants, because carboxylation of the anticoagulant regulatory proteins S as well as C blocked by them. Carboxylation changes the conformation of coagulation proteins in the presence of calcium ions, enhancing binding to cofactors on phospholipid surfaces 54 .
Administration of vitamin K antagonists exhausts vitamin KH2, leading to the inhibition of -carboxylation of VKD coagulation proteins. Since the last stage of reductase framework is comparatively unsusceptible towards the antagonists of the K vitamin, vitamin K1 (ingested or supplied clinically) can prevent the impact of coumarins. In hepatocellular regions, the K1 vitamin concentrates and seems to be ready for reductase that is unsusceptible to coumarin 55 .

Anti-metabolic syndrome Potential of Natural Coumarins
A novel coumarin called dihydromammea C/OB (R36) was extracted first from seeds of the Mammea africana Sabine (Guttiferae) tree in West Africa 56 . Stem barks' extracts of Mammea africana, prepared by employing dichloromethane and methanol as extracting solvents, have exhibited antihypertensive effects with N -nitro-L-arginine methylesterproduced hypertension in males albino rats. The rats used in this trial weighed between 300 and 250 grams and were 16 to 12 weeks old 57 . Also, both of the previous mentioned extracts have displayed enhanced positive modifications in the metabolism as well as considerable anti-hyperglycemic impact through streptozotocin-stimulated diabetic males albino rats 58 . Coumarin itself has also been shown to have vasodilatory impact in cultivated myocytes 59 .
An active component named visnadine and derived from Ammi visnaga, especially from its corresponding fruit, has been traditionally used to treat angina pectoris. This coumarin product possesses peripheral and coronary vasodilator properties 60 .
R34 is a smooth muscle relaxant that was extracted from Tetrapleura Tetraptera Taub of the family named Mimosaceae, especially from its corresponding fruit. R34 causes hypotension among lab mice both in vivo & in vitro 6 . Additionally, Khellactone (R37) was also found to have vasodilatory properties, and was discovered in Phlojodicarpus sibiricus 61 .

Anticancer Potential of Natural Coumarins
R42 has the anticancer potential 63 and can prevent N-methyl-D-aspartate toxicity in cultured primary neurons 64 . Also, R4 was also found to have antitumor activity 65 , while R1 discovered to have cytotoxic effects when extracted from cassia leaf oil 12 . From another point of view, R39 was found to protect human umbilical vein endothelial cells from hydrogen peroxide-induced cytotoxicity 66 .
R9, through wound healing and transwell experiments, showed that it could suppress the breast malignant cells' spreading and invading. This coumarin can suppress matrix metalloproteinase-s promoter and luciferase, which could be one of the reasons for R9's prevention of migration and invasion 67 .
R13 has been demonstrated to be an anticancer in murine L1210 and B16 melanoma, as well as P388 leukemias 68 . 3"-Demethylchartreusin (R43) is an unprecedented anti-neoplastic antibiotic generated by Streptomyces chartreusis, comprising similar aglycone but different sugar groups. It's a chartreusin structural equivalent 68 .
Finally, R6, R7, R8, and R9 were slightly cytotoxic toward the A549 lung cancer cell line. All four were extracted from the plant named Ferulago campestris 8 .

Antioxidant Potential of Natural Coumarins
R42 was found to be a promising antioxidant in many research reports 69 . Also, R40, at elevated concentrations (0.5mM), demonstrated free radicalscavenging potential, as well as cell protection against hydrogen peroxide mediated oxidative stress 66 . Besides, R42 and R39 that found in the fruits and stems of Actinidia chinensis and Actinidia deliciosa (kiwifruit) have revealed a noted activity as antiradicals versus several damaging free radicals 70 . Moreover, R6, R7, R9, and R8, had all been assessed for their antioxidant potential, using whole blood leukocytes and isolated polymorphonucleated chemiluminescence in humans 16 .

Anti-Inflammatory Potentials of Natural Coumarins
It is found that R1 has anti-inflammatory features and can be utilized to treat edema by promoting phagocytosis, enzyme synthesis, and consequently proteolysis, which eliminate protein and edema fluid from wounded tissue 71 .
R4, another coumarin-based product, has anti-inflammatory potential in a carrageenan-invigorated murine-paw edema fashion in vivo and lipopolysaccharide-induced murine macrophages in vitro. Through these assays, R4 can inhibit the production of a protein of both cyclooxygenase-2 as well as nitric oxide synthase of inducible type 72 .
R42 has demonstrated anti-inflammatory potential in rat colitis caused by trinitrobenzene-sulfonic acid 73 74 . This coumarin-based product was derived from Bougainvillea spectabilis Wild 4 and Cichorium intybus 18 . It can block the enzymes of the inflammatory response including cyclooxygenases and lipoxygenases, as well as superoxide anion production in neutrophils 75 .

Anticonvulsant Potential of Natural Coumarins
It is reported that R4 may exhibit an anticonvulsant activity in mice, with ED50 values ranging from 290 to 167 milligram per kilogram. The R4's TD50 readings spanning from 329 to 443 mg/kg, according to severe neurotoxicity impacts of chimney experiment 35 . Also, R9 may exhibit an anticonvulsant activity in mice, with ED50 values ranging from 253 to 639 mg/kg and acute neurotoxicity spanning from 531 to 648 mg/kg 76 .

R42,
when given intracerebroventricularly 30 minutes at a concentration of 20 g/ml prior to ischemia, can exhibit neuroprotective benefits in a middle-cerebral artery blockage in mice fashion 77 .

Methoxsalen )R44( was identified in
Umbelliferae family products, specifically in the seeds of the plant Ammi majus, also demonstrated in vitro potency as a microsomal P-450 inhibitor 78 , as well as impacted on human cytochrome P-450 2A6 efficiency with a single dosage 79 .

Multiple sclerosis treatment with Natural Coumarins
It is proposed and reported that the coumarin-based product symbolized as R9 can represent as a medicinal therapy in patients with multiple sclerosis 80 .

Natural Coumarins functionalized as phytoalexins
Plants create phytoalexins, some of them are derived from coumarin chemical nucleus, in response to pathological processes like fungal infection, chemical injury, as well as physical harm. Invading elements, including viruses, insects, and bacteria, are typically suppressed or killed by phytoallexins 81

Coumarin Detection from Numerous Sources and Their Structural Description
Coumarin-based products can present in different parts of various plants, and Table 3 gives a simple idea about that.

Coumarins-Analysis Using Various Techniques
Chromatography-dependent techniques involving high-performance liquid chromatography(HPLC), gas chromatography(GC), thin-layer chromatography (TLC), and paper chromatography (PC), spectrophotometry-dependent methods including polarographic and colorimetric, and titrimetric methods are all used to isolate and analyze natural coumarins 90 .