INTRODUCTION:

Coumarin is derived from the name of a class ‘Coumarou’, the regional name of the tonka bean (Dipteryx odorata Willd, Fabaceae) which was recognized in 1820. Coumarins are pharmacologically active moiety well known for their wide variety of activities. Coumarin is the combination of benzene and pyrone ring and it belongs to benzo pyrone family. It is available from plants, microorganisms etc.

Depending on various substitutions on different positions of coumarin, we get different pharmacological properties like anticancer, antioxidant, antifungal, anti-inflammatory, antiviral, anticoagulant etc^1,2,3,4. Coumarins consist of a considerably big class of compounds available all over the plant kingdom. They are available at elevated levels in several essential oils, remarkably lavender oil, cassia leaf oil (up to 87,300 ppm) and cinnamon bark oil (7,000 ppm). Also, they are available in fruits (e.g. bilberry, cloudberry), green tea and other foods namely chicory. Majority of the coumarins transpire in higher plants, wherein the most affluent origins happen to be the Umbelliferone and Rutacea. Even though coumarins are circulated to each and every part of the plant, they happen to be transpired at the elevated levels in the fruits, and then the roots, stems and leaves. The transpiration in diverse parts of the plant can be influenced by environmental conditions and seasonal changes. From the stem bark of Calophyllum dispar (Clusiaceae) and the fruits, six fresh trivial coumarins are identified in the recent times. Even though majority of the natural coumarins currently existing are identified from higher plants, several constituents are tracked down in micro-organisms. Several of the salient coumarin constituents are identified from microbial sources e.g. aflatoxin from Aspergillus, and coumermycin and novobiocin from Streptomyces species. Coumarins happen to be a familiar class of peripheral metabolites in plants ^5,,6 and fungi^7,8. Taking into account the structural features of coumarins, they are a major classification of substrate in the sectors of synthetic chemistry^9,10and natural product alteration.

For the first time in the early 1920’s, the study with respect to the coumarin compounds began when Schofield¹⁰ reported a fresh sickness in cattle - “sweet clover disease” - related with defective coagulation. Subsequently in the recent times, due to the activities carried out by micro-organisms, it was manifested that the disorder has been created by variations transpiring in inappropriately rehabilitated hay procured from sweet clover^11,12,13. In 1922, a considerable step ahead was taken when this disorder was ushered to the recognition to Link. Also, invincible assurance was achieved^14,15,16 furnishing the compound specified as 3, 3’-methylenebis (4-hydroxycoumarin) (Dicumarol). Currently it is one of the extensively utilized oral anti-coagulants after being synthesized. Bingham et al.¹⁷and Butt and associates created the maiden clinical application. In 1948, a vigorous synthetic derivative, 3-(α-acetonylbenzyl)-4-hydroxycoumarin got created and it had been named as warfarin in the honor of Wisconsin Alumni Research Foundation. In the beginning, warfarin was extensively utilized as a rodenticide due to the scrutinizes of impermissible morbidity. Later, an army inductee monotonously got through a great overdose of a warfarin rodenticide in 1951. In 1955, warfarin was again used to nurse President Eisenhower when he suffered a heart attack furnishing to the common affirmation of warfarin as a therapeutic drug. Phenprocoumon and Acenocoumarol are not in use in the United States, but they are being utilized in different other regions of the world. These three drugs are 4-hydroxycoumarin derivatives with non-polar carbon side-chains at position three. Inspite of being available, Indane-1,3-dione oral anticoagulants are not used persistently therapeutically. Since the 1970s, “superwarfarins” have come into use because of the invulnerable effect of warfarin on several rat populations. Superwarfarins are the rodenticides that have higher vigour and substantially prolonged half-lives when compared to the warfarin and other therapeutic vitamin K antagonists (VKA). In the recent times, many oral anticoagulants (NOACs) are evolved that comprise of direct thrombin (II) inhibitor dabigatran and direct activated factor Xa inhibitors (apixaban, edoxaban, rivaroxaban). These are the anti-coagulants imposed with fixed dosing and no requirement of being observed systematically. The marketing of these are done to provide enhanced attributes incorporating smaller relation between food and drug, quicker inception of operation, and fugitive half-lives of eradication^18,19,20.

Chemical Structures of Some Anti-coagulant Drugs:

Blood Coagulation and Anticoagulant:

Fluidity of blood is controlled by the physiological systems which are both complex and elegant. At sites of vascular injury, blood must prevail as a liquid inside the vasculature and also clot swiftly when exhibited to surfaces that are not endothelial. To restore fluidity of blood when intravascular thrombus takes place, a system of fibrinolysis is actuated. Both thrombosis and hemorrhages are averted by an elegant equilibrium which also admits physiological fibrinolysis with no excessive pathological fibrinogenolysis. Efficacy and toxicity are essentially interwoven with these drugs. Considering an example, overdosing of anticoagulant can lead to the offset of desired therapeutic effect of anti-coagulation by the toxic effect of bleeding. Likewise, systemic destruction of fibrinogen and coagulation factors is provided a direction by overstimulation of fibrinolysis. The principal agents for controlling fluidity of blood include parenteral anti-coagulant heparin and its derivatives. Vitalization of a natural inhibitor of coagulant proteases is done by those principal agents. Multiple steps in coagulation cascade are obstructed by coumarin used as anti-coagulants. Vitamin-K’s aggressive inhibitors in the biosynthesis of prothrombin are coumarins. The coagulation cascade depends on the Transformation of prothrombin to thrombin is dependable on coagulation cataract in a very key step under the condition^21,22,23.

Mechanism of Action:

Coumarins hinder post-translational carboxylation of glutamate residues on proteins based on vitamin K which includes the coagulation factors II, VII, IX, and X. This procedure of carboxylation is necessary for their biological activity and demands diminished configuration of vitamin K. Vitamin K epoxide reductase, the enzyme which is accountable for the reprocessing of vitamin K, is also hindered by coumarins. Recognition of vitamin K epoxide reductase complex 1 (VKORC1) gene was done in recent times, which in turn has granted the research of the result of polymorphisms on reactivity to coumarins. The metabolism of warfarin is primarily dependent on hepatic microsomal enzyme P450 2C9 (Cyp2C9), which catalyzes deterioration of the better potential S enantiomer to inactive metabolites^24,25,26.

Variations in Anti-coagulant Effect:

There are considerably less side effects from the coumarins. Nevertheless, so far abnormal bleeding is the most familiar undesired effect which may turn out to be lethal. In spite of the global validation of International Normalized Ratio as the method for standardization of the prothrombin time and the coagulation assay utilized to measure the anti-coagulant result of warfarin, this side effect of abnormal bleeding still exists. For majority of the clinical indications, the dosage is directed at attaining a goal International Normalized Ratio of 2.5 (range 2.0–3.0), that constitutes a level of anti-coagulation based on favorable correlation intermediate of anti-thrombotic efficacy and bleeding risk. With the finest handy regulation, discrete victims on warfarin are inside the goal International Normalized Ratio scale for about 50%–70% of the time, on par. Even though motives for this inaccuracy in the reciprocation of dosage are most of the times not instantly apparent, significant donating strands include co-medication with interrelating drugs²⁷ and non-finished adherence.

Coumarins process their anti-coagulant effect by hindering vitamin K transformation cycle, thereby resulting in hepatic production of semi-carboxylated and de-carboxylated proteins with decreased pro-coagulant activity. The coumarins’ effect can be prevented by vitamin K₁ because the second reductase step is respectively inconsiderate to vitamin K adversaries. Victims served with a big dose of vitamin K₁ can also become resistant to warfarin for up to a week. This is because vitamin K₁ piles up in the liver and is handy to the coumarin-insensitive reductase.

Across the years, heparin and warfarin are the 2 drugs that are in high demand. These drugs may be effective and also often result in drastic side effects which include serious bleedings. Many turnaround agents are obtainable for victims terribly affected from consuming warfarin. Usage of heparin has resulted to low platelet levels which can lead to new clots in the blood vessels and can also usher to stroke or heart attack. Whereas, blood is made comparatively simply “too thin” by warfarin which escalates the possibility of occurrence of brain hemorrhage, which is a category of stroke resulted by bleeding in the brain. Adding to the above mentioned catastrophic results, use of anti-coagulants concludes in several minute raucous side effects such as passing of blood in the urine, severe skin injury that results in lengthened nosebleeds, bleeding gums, discoloration of the skin or severe periods in women.

The Pharmacodynamics of Warfarin in Man:

In 1948, Link²⁸proposed that coumarin compound warfarin shall be utilized as a rodenticide. In 1952, the introductory human usage was in a suicide attempt. Even though, warfarin was enlisted increasingly in the nursing of thrombo-embolic problems, the observed printed details of its physiologic constitution in man is null, most likely owing mainly to the deficiency of an appropriate technique for computation of warfarin in biologic fluids²⁹.

Burns³⁰,Brodie and Weiner and asserted that “The half-life of warfarin in man is 90 hours, but did not include the assay method, or give supporting data”. In 1953, Umezu, Goto and Yuyama reported a colorimetric technique for warfarin evaluation in the plasma of rat whereas evidently this technique was not at all experimented on man. Since 1954, including the studies of Garner³¹, Eble, and Lin, many investigations of warfarin on rat has been observed. Their techniques were not printed excluding the doctoral thesis, or they were not willingly compliant for studies in man. In the recent times, a spectro-photometric technique for warfarin evaluation in biologic fluids was researched. This technique was utilized for the investigation of warfarin’s pharmacodynamics in man. The warfarin’s concentrations were dictated in plasma and of warfarin metabolite in urine of typical patients after both oral and intravenous management of the antidote. Examination of data furnished particulars on the absorption, elimination, apparent distribution volume and excretion of warfarin. Contrasts in the biologic effect of warfarin were estimated by concurrent assessment of warfarin’s plasma concentration and of prothrombin complex activity.

CONCLUSION:

The activity of the coumarin-type antidotes and allied compounds is assessed with discrete testimonial to their “prothrombinopenic” results, to their metabolism, excretion, and several irregularities pertinent to their activities relevant to their empirical therapeutic usage. Direct factor Xa inhibitors and direct thrombin inhibitors display assuring outcomes in diagnostic trials of stroke interception to be treasured substitutes to vitamin K adversaries in the forthcoming. Launch of these inventive materials to trade has been a significant milestone in the advancement of sheltered and victim-oriented plans for oral anti-coagulation. For decades together, vitamin K adversaries have been the sole curative option for oral anti-coagulation among victims with atrial fibrillation and an elevated fear of cerebral embolism. There is requirement for fresh substances with a commendatory pharmacological profile because of numerous drawbacks of vitamin K adversaries which includes regular coagulation observing, relatedness with food, and numerous drugs and bleeding problems. Currently, the finest proof is obtainable for dabigatran and rivaroxaban. The advancement of latest curatives turns out to be highly significant in the nursing of thrombo-embolic strokes, which most of the times cause critical functional disability and neurological sequela, such as post-stroke dementia or post-stroke epilepsy. Even though a lot of victims are previously nursed with fresh thrombin inhibitors and factor Xa inhibitors, these latest oral anti-coagulants require additional investigation in post-consent research beneficial to estimate the cohesion of nursing in “real-life” surroundings and security features in distinct subspecies of victims. Exceptional priority is placed on the significance of characterization in administration, and of finished apprehension on the portion of the medic with respect to several physiologic, pharmacologic and pathologic aspects relevant to anti-coagulant remedy.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of NITTE (Deemed to be University) for providing the facilities.

REFERENCES:

1. Thomas R. Hari R. Joy J. Krishnan S. Swathy AN. Nair SS. Manakadan AA et al In silico Docking Approach of Coumarin Derivatives as an Aromatase Antagonist. Research Journal of Pharmacy and Technology. 2015; 8(12):1673-78. DOI:10.5958/0974-360X.2015.00302.9

2. Sandeep G. Ranganath YS. Bhasker S. Rajkumar N. Synthesis and Biological Screening of Some Novel Coumarin Derivatives. Asian J Research Chem. 2009; 2(1):46-48.

3. Monika N. Verma R. Sharma SK. Synthetic Study of Vitamin K3 (Menadione, 2-methyl-1, 4-naphthoquinone): A Review. Asian J Research Chem. 2012; 5(9):1200-04.

4. Jainab NH. Sivachidambaram P. Yuvaraju J. Beyatricks J. Raj B Microwave Mediated Synthesis, Characterisation and Biological activity of Certain New Mannich Bases of Isatin and Coumarin. Asian J Research Chem. 2014; 7(2):176-81.

5. Braun AE. Gonzalez AG. Coumarins. Natural Product Reports. 1997; 5:433–558. https://doi.org/10.1039/NP9971400465

6. Murray RDH. Coumarins. Nat Prod Rep. 1995; 5:445–554.

7. Xu J. Kjer J. Sendker J. Wray V. Guan H. Edrada R. Muller WEG et al Cytosporones, coumarins, and an alkaloid from the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophoramucronata. Bioorganic and Medicinal Chemistry. 2009; 17:7362–67. https://doi.org/10.1016/j.bmc.2009.08.031

8. Yang XL. Awakawa T. Wakimolo T. Abe I. Induced production of novel prenyldepside and coumarins in endophytic fungi Pestalotiopsis acacia. Tetrahedron Letters. 2013; 54:5814–17. DOI: 10.1016/j.tetlet.2013.08.054

9. Biswas B. Sen PK. Venkateswaran RV. Bargellini condensation of coumarins. Expeditious route to o-carboxyvinylphenoxyisobutyric acids and application to the synthesis of sesquiterpeneshelianane, heliannuol A and heliannuol.Tetrahedron. 2007; 63(48):12026–36. DOI: 10.1016/j.tet.2007.09.006

10. Khan AT. Das DK. Islam K. Das P. A simple and expedient synthesis of functionalized pyrido [2, 3-c] coumarin derivatives using molecular iodine catalyzed three-component reaction. Tetrahedron Letters. 2012; 53:6418–22. https://doi.org/10.1016/j.tetlet.2012.09.051

11. Schofield FW. A brief account of a disease in cattle simulating hemorrhagic septicemia due to feeding sweet clover. Canadian Journal of Veterinary Research. 1984; 25(12):453-5.

12. Roderick LM. The pathology of sweet clover disease in cattle. Journal of the American Veterinary Medical Association. 1929; 74:314-25.

13. Momin KI. Suryawanshi VB. Bondge AS. Dawale JK. Synthesis and biological evaluation of coumarin acetamide derivatives. Asian J Research Chem 2018; 11(2):453-58. http://dx.doi.org/10.5958/0974-4150.2018.00082.2

14. Arora P. Ranawat MS. Arora N. Synthesis and Screening of Some Novel Coumarin Derivatives for Antipsychotic Activity. Research J Pharm and Tech. 2012; 5(7):968-72.

15. Campbell HA. Link KP. Studies on the hemorrhagic sweet clover disease. IV. The isolation and crystallization of the hemorrhagic agent. Nutrition Reviews. 2009; 32(8):244-46.

16. Thomas R. Hari R. Joy J. Krishnan S. Swathy AN. Nair SS. Manakadan AA et al In silico Docking Approach of Coumarin Derivatives as an Aromatase Antagonist. Research J Pharm and Tech. 2015; 8(12):1673-78. http://dx.doi.org/10.5958/0974-360X.2015.00302.9

17. Kumar A. Shetty P. Amrutha CL. Vaz DR. Baby A. Synthesis and Antimicrobial Evaluation of Some Novel Derivatives of Coumarin Moiety. Research J Pharm and Tech. 2016; 9(5):545-48. https://doi.org/10.5958/0974-360X.2016.00103.7

18. Bingham JB. Meyer OO. Pohle FJ. Studies on the hemorrhagic agent 3,3’-methyl-enebis (4-hydroxycoumarin). I. Its effect on the prothrombin and coagulation time of the blood of dogs and humans. American Journal of the Medical Sciences. 1941; 202:563-78.

19. Butt HR. Allen EU. Bollman JL. A preparation from spoiled sweet clover 3,3’-methyl-enebis (4-hydroxycoumarin) which prolongs coagulation and prothrombin time of blood:preliminary report of experiments and clinical studies. Proceedings of the Staff Meeting Mayo Clin. 1941; 16:388-95.

20. Nair NP. Allen EU. Bollman JL. In-silico Docking Studies of Coumarin Derivatives as Caspase 8 and PDE4 Antagonist. Research J Pharm and Tech. 2016; 9(12):2199-2204. https://doi.org/10.5958/0974-360X.2016.00445.5

21. Kumar A. Kumar P. Pinto JS. Bhashini. Akshata. Synthesis and Antimicrobial Evaluation of Some new Coumarinyl Schiff Base Derivatives. Research J Pharm and Tech. 2018; 11(11):4946-48. http://dx.doi.org/10.5958/0974-360X.2018.00900.9

22. Li T. Chang CY. Jin DY. Lin PJ. Khvorova A. Stafford DW Identification of the gene for vitamin K epoxide reductase. Nature. 2004; 427:541–44. https://doi.org/10.1038/nature02254

23. Naasani N. Harbali J. Kandil F. Synthesis and Biological Evaluation of 3-thiosemicarbazoneacetyl Coumarin derivatives as Antioxidant. Research J Pharm and Tech. 2020; 13(10):4565-69. https://doi.org/10.5958/0974-360X.2020.00804.5

24. Debasish S. Tripti S. Molecular Docking studies of 3-substituted 4-phenylamino coumarin derivatives as Chemokine receptor inhibitor. Research J Pharm and Tech. 2021; 14(2):943-48. https://doi.org/10.5958/0974-360X.2021.00168.2

25. Panneerselvam S. Baglin C. Lefort W. Baglin T. Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin. British Journal of Haematology. 1998; 103:422–24. https://doi.org/10.1046/j.1365-2141.1998.00988.x

26. Kavitha K. Sree BK. Preethi JP. Kumar PK. Rajvel R. Sivakumar T. Synthesis, Characterization and Biological Activity of Coumarin Derivatives. Research J Science and Tech. 2012; 4(6):252-57.

27. Lubetsky A. Dekel-Stern E. Chetrit A. Lubin F. Haklin H. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thrombosis and Haemostasis. 1999; 81(3):396–99.

28. Link KP. The discovery of Dicumarol and its sequels. Circulation. 1959; XIX:97-107. https://doi.org/10.1161/01.cir.19.1.97

29. Holmes RW. Love J. Suicide attempt with warfarin, a bis-hydroxycoumarin-like rodenticide. Journal of the American Medical Association. 1952; 148(11):935-37. doi:10.1001/jama.1952.62930110003013a

30. Weiner M. Pharmacologic considerations of antithrombotic therapy. Advances in Pharmacol and Pharmacy. 1962; 1:277-307. https://doi.org/10.1016/S1054-3589(08)60511-6

31. Garner RJ. A spectroscopic study of the fate of warfarin and coumachlor in the rat. Nordisk Veterinary Medicine. 1957; 9:464.

Received on 11.02.2021 Modified on 15.06.2021

Research J. Pharm.and Tech 2022; 15(4):1659-1663.

DOI: 10.52711/0974-360X.2022.00277