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Journal ArticleDOI

Recent advances and therapeutic journey of coumarins: current status and perspectives

TL;DR: The occurence, synthesis and specific biological activities of various coumarin derivatives are described for the discovery and development of new synthetic strategies that could help in structure–activity relationship (SAR) studies.
Abstract: Coumarins are oxygen-containing molecules with specific benzopyrone nucleus. Different coumarins are identified as antineurodegeneratives, anticoagulants, antioxidants, antimicrobials, anticancers, antivirals, antidiabetics, antidepressants, supramoleculars, antiparasitics, anti-inflammatory, analgesics, biological stains, pathological probes and diagnostics. Coumarins have received more attention as compared to 1-azacoumarins. Many attempts have been made for the comparison of both the systems at different stages to discover novel synthetic methodologies, reactivity strategies and biological activities. Translation of current knowledge into novel potent lead compounds and repositioning of well-known compounds for the treatment of different acute and chronic diseases are the current challenges of coumarins. This review article focusses on the occurence, synthesis and specific biological activities of various coumarin derivatives. Some novel research approaches are also described for the discovery and development of new synthetic strategies that could help in structure–activity relationship (SAR) studies. Cellular and molecular mechanisms of coumarins involved in SAR studies are also described.
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Journal Article

1,633 citations

Journal ArticleDOI
TL;DR: An overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations.
Abstract: Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. As a consequence, a huge number of coumarin derivatives have been designed, synthesized, and tested to address many pharmacological targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer’s and Parkinson’s diseases. In this review an overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations. The many existing and recent reviews in the field prompted us to make some drastic selections, and therefore, the review is focused on monoamine oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected targets of neurodegenerative diseases.

349 citations


Cites background from "Recent advances and therapeutic jou..."

  • ..., the coumarin scaffold characterizes a large variety of biologically active natural products, pharmaceuticals, agrochemicals, and polymeric [2] and optoelectronic [3] materials....

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  • ...Industrial interest on coumarins led to the development of cosmetics, agrochemicals, polymeric [2], and optoelectronic materials [3]....

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Journal ArticleDOI
TL;DR: This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches.
Abstract: Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches.

125 citations


Cites background from "Recent advances and therapeutic jou..."

  • ...The former one faces phase II conjugation reaction resulting in the glucuronide derivative, whereas 3-hydroxycoumarin can be further metabolized by ring splitting to form two products, o-hydroxyphenyllactic acid and ohydroxyphenylacetic acid (Figure 2) [4,21]....

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  • ...Since the expression of CYP2A6 varies between individuals, due to genetic and e viro me tal factors, an inter-individual v riation in the metabolism f coum rin drugs is pos ible [4]....

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  • ...The history of these natural products began 200 years ago—the name of the class derived from the plant Coumarouna odorata (Dipteryx odorata) from which the simplest member of this family, coumarin itself (Figure 1), was isolated by Vogel in 1820 [3,4]....

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  • ...Since the expression of CYP2A6 varies between individuals, due to genetic and environmental factors, an inter-individual variation in the metabolism of coumarin drugs is possible [4]....

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  • ...The former one faces phase II conjugation reaction resulting in the glucuronide derivative, whereas 3-hydroxycoumarin can be further metabolized by ring splitting to form two products, o-hydroxyphenyllactic acid and o-hydroxyphenylacetic acid (Figure 2) [4,21]....

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Journal ArticleDOI
Liang Yang1, Wei Ding1, Yuquan Xu, Dousheng Wu1, Shili Li1, Juanni Chen1, Bing Guo1 
TL;DR: It is demonstrated that hydroxycoumarins have superior antibacterial activity against the phytopathogen R. solanacearum, and thus have the potential to be applied for controlling plant bacterial wilt.
Abstract: Coumarins are important plant-derived natural products with wide-ranging bioactivities and extensive applications. In this study, we evaluated for the first time the antibacterial activity and mechanisms of action of coumarins against the phytopathogen Ralstonia solanacearum, and investigated the effect of functional group substitution. We first tested the antibacterial activity of 18 plant-derived coumarins with different substitution patterns, and found that daphnetin, esculetin, xanthotol, and umbelliferone significantly inhibited the growth of R. solanacearum. Daphnetin showed the strongest antibacterial activity, followed by esculetin and umbelliferone, with MICs of 64, 192, and 256 mg/L, respectively, better than the archetypal coumarin with 384 mg/L. We further demonstrated that the hydroxylation of coumarins at the C-6, C-7 or C-8 position significantly enhanced the antibacterial activity against R. solanacearum. Transmission electron microscope (TEM) and fluorescence microscopy images showed that hydroxycoumarins may interact with the pathogen by mechanically destroying the cell membrane and inhibiting biofilm formation. The antibiofilm effect of hydroxycoumarins may relate to the repression of flagellar genes fliA and flhC. These physiological changes in R. solanacearum caused by hydroxycoumarins can provide information for integral pathogen control. The present findings demonstrated that hydroxycoumarins have superior antibacterial activity against the phytopathogen R. solanacearum, and thus have the potential to be applied for controlling plant bacterial wilt.

98 citations


Cites background from "Recent advances and therapeutic jou..."

  • ...Coumarins have been proven to have multiple substitution sites, and different substitutions in these sites significantly affect the biological activity of coumarins [16,21,22]....

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  • ...Which include antibacterial, antifungal, anticoagulant, antioxidant, anticancer, and anti-inflammatory properties [16,17]....

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Journal ArticleDOI
TL;DR: Detailed quantitative structure-activity relationship (QSAR) analysis indicated the molecular parameters that contribute to increased potency of inhibition and would further encourage understanding in employing coumarin pyrazole hybrids as potential antibiotic agents for treating infections caused by pathogenic microbes and fungi.

97 citations

References
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Journal ArticleDOI

2,678 citations


"Recent advances and therapeutic jou..." refers background in this paper

  • ...As compare with alkaloids synthesized through shikimic acid pathways, many compounds in which the nucleus is alkylated by one or more isoprenoid units (Barton and Ollis, 1979)....

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Journal Article

1,633 citations


"Recent advances and therapeutic jou..." refers background in this paper

  • ...Induction of apoptosis produces potent inhibitory effect of compound 49 through activating Bax, p53 and p21 expression in a dose-dependent manner (Kim et al., 2010)....

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  • ...…gastric cancer cells with IC50 value of 42.70 lM and inhibited the proliferation of the AGS cells at rate of about 54 % at 100 lM. Induction of apoptosis produces potent inhibitory effect of compound 49 through activating Bax, p53 and p21 expression in a dose-dependent manner (Kim et al., 2010)....

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Journal ArticleDOI
19 Jan 2000-JAMA
TL;DR: The availability of new antiretroviral drugs has expanded treatment choices and the importance of adherence, emerging long-term complications of therapy, recognition and management of antireTroviral failure, and new monitoring tools are addressed.
Abstract: Objective To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. Participants A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society–USA in December 1995. Evidence Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. Consensus Process The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. Conclusions The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

1,066 citations


"Recent advances and therapeutic jou..." refers methods in this paper

  • ...4-Phenylcoumarins 22 and 23 were isolated from Marila pluricostata (Carpenter et al., 2000) and were found to suppress HIV-1 replication in Jurkat T cells....

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Journal ArticleDOI
TL;DR: Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions.
Abstract: 1. 1. More than 1300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. More complex related compounds based on the coumarin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxins and the psoralens (photosensitizing agents). 2. 2. Coumarin itself (1,2-benzopyrone) has long-established efficacy in slow-onset long-term reduction of lymphoedema in man, as confirmed in recent double-blind trials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage-induced proteolysis of oedema protein. However, coumarin has low absolute bioavailability in man (<5%), due to extensive first-pass hepatic conversion to 7-hydroxycoumarin followed by glucuronida. tion. It may, therefore, be a prodrug. 3. 3. Scoparone (6,7-dimethoxycoumarin) has been purified from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear cells, to relax smooth muscle, to reduce total cholesterol and triglycerides and to retard the characteristic pathomorphological changes in hypercholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to scavenge reactive oxygen species, inhibition of tyrosine kinases and potentiation of prostaglandin generation. 4. 4. Osthole (7-methoxy-8-[3-methylpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese medicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. 5. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic antiplatelet actions, inhibits PMN neutrophil function and causes vasodilatation. Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. 6. Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions. These coumarins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromolar concentrations. Another related coumarin, 5, 7-dihydroxy-4-methylcoumarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simple coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hypochlorous acid, and is a potent inhibitor of cyclo-oxygenase, but is not pro-oxidant. 7. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin both reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen-derived free radicals are implicated), showing that these antioxidant coumarins possess beneficial properties in this pathophysiological model. 8. 8. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

874 citations


"Recent advances and therapeutic jou..." refers background in this paper

  • ...5-LOX represents a dioxygenase that possesses two distinct enzymatic activities leading to the formation of LTA4, which is converted to 5-hydroxyeicosatetraenoic acid (5-HETE) or five lipoxygenase activating protein (FLAP) (Hoult and Paya, 1996a, b)....

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  • ...Coumarins (1,2-benzopyrone) have fused benzene and a-pyrone rings which are present in specific amounts in plants and more than 1300 coumarins were identified from natural sources (Hoult and Paya, 1996a, b)....

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Journal ArticleDOI
TL;DR: The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscou marins and triscoumarins.
Abstract: Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.

821 citations


"Recent advances and therapeutic jou..." refers background or methods in this paper

  • ...This system was used for the preparation of esterase-sensitive prodrugs of amine-containing compounds or peptides (Wang et al., 1996a, b; Borges et al., 2005a, b)....

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  • ...3; Borges et al., 2005a, b)....

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  • ...New fluorescent probes of novel coumarins are developed by fluorescent spectroscopic studies, which are applied either in water or in micelles (Borges et al., 2005a, b; Baloglu et al., 2001)....

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