Abstract Viral infections are responsible for many illnesses, and recent outbreaks have raised public health concerns. Despite the availability of many antiviral drugs, they are often unsuccessful due to the generation of viral mutants and less effective against their target virus. Identifying novel antiviral drugs is therefore of critical importance and natural products are an excellent source for such discoveries. Coumarin is one such natural compound that is a potential drug candidate owing to its properties of stability, solubility, and low toxicity. Introduction Viruses pose a global threat and add serious medical and social problems to the mankind.

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Introduction Phytochemicals are chemical compounds that occur naturally in the plant kingdom. Some are responsible for the organoleptic properties of the natural sources in which they are present. The term is generally used to refer to those chemicals that may have biological significance, for example carotenoids, flavonoids, coumarins, or chromones, but not all are established as essential nutrients. There may be as many as 4, different phytochemicals having potential activity against several diseases such as cancer and metabolic or degenerative diseases.

Among them, coumarins are a family of benzopyrones 1,2-benzopyrones or 2Hbenzopyranones widely distributed in the nature. Figure 1. It has a sweet odor, easy to be recognized as the scent of new-mown hay; because of that, coumarin has been used in perfumes since It is presumed to be produced by plants as a chemical defense to discourage predation [ 2 , 3 ].

The simplicity and versatility of the coumarin scaffold make it an interesting starting-point for a wide range of applications [ 6 - 8 ]. There are coumarins as perfumes, cosmetics, and industrial additives. Some of its derivatives have been used as aroma enhancers in tobaccos and certain alcoholic drinks [ 9 , 10 ].

But their most relevant role is described in natural products, organic chemistry, and medicinal chemistry [ 11 , 12 ]. The extraction, synthesis, and evaluation of coumarins have become an extremely attractive and rapidly developing topic [ 13 , 14 ].

Moreover, a lot of coumarin compounds as medicinal candidates for drugs with strong pharmacological activity, low toxicity and side effects, fewer drug resistance, high bioavailability, broad spectrum, better curative effects, etc. Several efforts have been made mainly in developing coumarin-based anticoagulant, antioxidant [ 16 ], antimicrobial anti-viral, antifungal, and anti-parasitic [ 10 , 17 ], anticancer [ 18 - 20 ], anti-diabetic, analgesic, anti-neurodegenerative, and anti-inflammatory agents [ 10 , 21 ].

Moreover, the unique and versatile oxygen-containing heterocyclic structure makes coumarin compounds occupy an important place in medicinal chemistry [ 22 , 23 ].

In addition, studies have been done regarding coumarins as bioactive agents [ 24 ], as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains [ 25 ]. Particularly, the large - conjugated system in the coumarinic ring, with electron-rich and charge-transport properties, is important in the interaction of this scaffold with molecules and ions.

Coumarin-based ion receptors, fluorescent probes, and biological stains are growing quickly and have extensive applications to monitor timely enzyme activity, complex biological events, as well as accurate pharmacological and pharmacokinetic properties in living cells [ 26 , 27 ].

Coumarin was first synthesized in , and it was used in the pharmaceutical industry as a precursor in the synthesis of a number of synthetic anticoagulant pharmaceuticals, starting with dicoumarol removed from the current therapy [ 28 ]. So far, some interesting coumarin-based anticoagulant drugs have extensively been used in clinics [ 29 ]. Coumarins are a type of vitamin K antagonists [ 30 ].

The most notable ones are warfarin, acenocumarol, and phenprocoumon, currently in use in several countries [ 31 , 32 ].

Warfarin is employed more frequently than acenocoumarol because of its longer half-life 36 h , theoretically providing more stable anticoagulation and avoiding factor VII fluctuations that potentially occur during acenocoumarol treatment half-life 10 h [ 33 ]. Nowadays, some coumarins proved to be enzymatic inhibitory agents [monoamine oxidase MAO inhibitors, acetylcholinesterase AChE inhibitors, and butyrylcholinesterase BuChE inhibitors] with great potential in neurodegenerative diseases ND [ 34 - 38 ].

Therefore, the coumarin ring is prevalently applied to construct several functional molecules in the medicinal field. A great deal of work has been done directed towards the separation and purification of naturally occurring biological coumarins from a variety of plants, animals, and microorganisms, as well as towards the artificial synthesis of coumarin compounds with novel structures and properties [ 42 ].

Coumarin compounds as medicinal drugs have been increasingly attracting special interest due to their underlying outstanding contributions in the prevention and treatment of diseases, and the related researches and developments have become an extremely attractive highlighted area. In this context, an overview of the role of coumarins as important phytochemicals and their interesting applications will be presented and discussed.

The origin, natural sources, biosynthesis, and applications are going to be presented in this chapter. Natural occurring coumarins Coumarin Figure 1 and its derivatives are an important group of natural compounds widely distributed in the natural kingdom [ 43 ]. They can be found in the integument of seeds, fruits, flowers, roots, leaves, and stems, although the largest concentration is generally in fruits and flowers [ 44 ]. Originally, coumarin was isolated from the seed of D.

Coumarins are secondary metabolites of higher plants, few microorganisms bacteria and fungi , and sponges [ 45 ]. The function of this type of end product of secondary metabolism is related to defense mechanisms against herbivores and attacks by microorganisms. These compounds are biosynthesized from phenylalanine via the shikimic acid [ 46 ]. Natural coumarins are generally unsaturated lactones and comprise another class of compounds C6C3.

Almost all the natural coumarins have an oxygenated substituent at position 7 [ 47 ], either free as in hydroxylated umbelliferone, or combined methyl, sugars, etc. Structurally, they are considered derivatives of the ortho-hydroxy-cinnamic acid. There are different classifications for the coumarin derivatives.

Generally, they can be chemically classified according to the most common cores: simple coumarins, complex coumarins, and various coumarins. More complex coumarins are generally fused with other heterocycles [ 3 ]. Therefore, they can be classified as: simple coumarins, furocoumarins, dihydrofurocoumarins, pyranocoumarins linear and angular , phenylcoumarins, and biscoumarins [ 1 ].

As said before, hundreds of coumarins have been identified in natural sources, especially plants [ 48 , 49 ]. Major coumarin constituents isolated from plants include: simple hydroxycoumarins, furocoumarins and isofurocoumarins, pyranocoumarins, biscoumarins, and dihydroisocoumarins Figure 2 [ 1 ]. Figure 2. Principal types of coumarins isolated from plants. Coumarins have been isolated from hundreds of plants species distributed in more than 40 different families.

There were isolated more than different coumarins, well distributed in Angiospermae, Monocotyledoneae and Dicotyledoneae families. The best known and researched coumarins in the field of phytochemistry, pharmacology, medicinal chemistry, and the food science can be found in these families.

Therefore, these are the coumarins that are going to be further addressed in the next sections of this chapter. Figure 3. Number of coumarins presented in seven different families of plants[50]. Coumarins usually are in the free state in plants as they are polar structures, and many of them can sublimate. They might also be found in the form of glycosides, including psoralen core-related structures [ 44 ].

They are characterized by UV light absorption, resulting in a very characteristic blue fluorescence; they are also very photosensitive as they can be altered by natural light [ 44 ]. These features are used in the isolation and analysis, as well as in unusual therapies such as photochemotherapy and the industry of chemical sensors [ 51 , 52 ].

Biosynthesis of coumarins Simple coumarins are biogenetically derived from shikimic acid, via cinnamic acid. Salix spp. Figure 4 explains the entire process [ 46 , 53 ]. Figure 4. Biosynthesis of simple coumarins. Pyrano and furocoumarins Figure 2 are also biogenetically derived from shikimic acid. These coumarins could be divided in two groups—lineal and angular—depending on the position where the isopentenyl pyrophosphate is condensed to further cyclize and form the heterocycle.

The biosynthesis of these complex coumarins could also be the result of the cyclization of a simple coumarin previously prenylated [ 53 ]. An approximation for the dicumarol biogenesis is the hydroxylation of the 4-position of the coumarin, that then captures a molecule of formaldehyde and is condensed with another molecule of 4-hydroxycoumarin, and finally enolize the keto group forming the dicumarol [ 46 ].

The second most prevalent coumarins are furocoumarins and pyranocoumarins. In the case of well-diversified structural types in Apiaceae and Rutaceae, coumarins are considered as chemotaxonomic markers [ 50 ]. Apiaceae is the major source of coumarins Figure 3 and one of the more diverse, containing five different types of coumarin derivatives simple coumarins, lineal furocoumarins, angular furocoumarins, lineal pyranocoumarins, and angular pyranocoumarins [ 50 , 54 ].

Rutaceae is also highlighted in both occurrence and diversification. Generally, the division Angiospermae is preferably rich in simple coumarins, followed by the furo and pyranocoumarins [ 50 ].

Coumarins in medicinal plants A large number of valuable species used commonly as medicinal plants, aromatic plants, and edible plants for human and animal feeding belongs to coumarin-rich plant families. Among them are species with well-documented biological activity, in which coumarins are part of the active principles. Coumarins presenting great pharmacological interest have been isolated in different geographical regions from other botanical families.

Also shown are the coumarin compounds having species and their yield if available. Most of these plants are well known by people and scientists as part of herbal medicine repertories in Europe, Asia, or the Americas [ 55 - 58 ]. From the list, several coumarin-containing species or genera have also ethnomedical records in Cuba and the Caribbean Basin [ 59 , 60 ]. Among of plant included are species with a great historical record of ethnomedicinal uses, and are present in traditional medicine systems: Ayurveda Medicine, Traditional Chinese Medicine and Unani Medicine, or in other recent cultures.

Also, renowned species used on conventional therapeutics and modern herbal medicine are included, ie. Coumarins are also present in several species belonging to different botanical families, which are widespread in the northeastern region of Brazil [ 61 ]. Some of them are reported in folk medicine as traditional remedies drugs for the treatment of respiratory diseases [ 55 ].

Many pharmacological activities have been ascribed to coumarins such as anticlotting, hypotensive, antimicrobial, anti-inflammatory, and antitumor activities [ 61 ]. Recent studies and review manuscripts regarding the coumarin scaffold describe the huge variety of biological activities that may be present in the natural coumarins [ 8 , 18 , 62 - 64 ].

Venugopala et al. Several recent reviews summarize and highlight advances in the application of coumarins, especially concerning their antioxidant and anticancer properties [ 62 - 70 ]. From Calophyllum spp. As active compound of molluscicidal effects on Biomphalaria glabrata of C.

Verticillatum [ 71 ]. It is the great structural diversity of coumarinic compounds that allows for their several applications, and also allows for the high interest of these derivatives as phytochemicals. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution [ 68 ].



Dushura Penile nitric oxide levels were also promoted, a mechanism that may enhance vasodilation and erectile function. Effect of total glucosides of Centella asiatica on antagonizing liver fibrosis induced by dimethylnitrosamine in rats. The method used by Takao et al. J Eur Acad Dermatol Venereol. Both annuals and perennial species occur ccoumarin this family, and even among the long-lived perennials, such as the Azorella that occurs in the Antarctic as a broad flat mat surviving for hundreds of years in harsh conditions, tough mineralization and a woody habit does not occur. Vasodilator effects of visnagin in isolated rat vascular smooth muscle.



Introduction Phytochemicals are chemical compounds that occur naturally in the plant kingdom. Some are responsible for the organoleptic properties of the natural sources in which they are present. The term is generally used to refer to those chemicals that may have biological significance, for example carotenoids, flavonoids, coumarins, or chromones, but not all are established as essential nutrients. There may be as many as 4, different phytochemicals having potential activity against several diseases such as cancer and metabolic or degenerative diseases. Among them, coumarins are a family of benzopyrones 1,2-benzopyrones or 2Hbenzopyranones widely distributed in the nature.


Coumarins — An Important Class of Phytochemicals

Kinos Beneficial effects of Foeniculum vulgare on ethanol-induced acute gastric mucosal injury in rats. Similar findings have been reported by other researchers. Platelet anti-aggregatory effects of coumarins from the roots of Angelica genuflexa and A. Centella has coimarin shown useful in promoting epithelial regeneration following burns. The healing effects of Centella extract and asiaticoside on acetic acid induced gastric ulcers in rats. Osthole improves aspects of spatial performance in ovariectomized rats.

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