Dicoumarol THE MOST COMMONLY USED DRUG

DICOUMAROL THE DRUG IS DESCRIBED IN THIS PRESENTATION WITH ITS MECHANISM OF ACTION, SYNTHESIS, SAR, AND ANALOGUES OF DICOUMARIL.

1. DICOUMAROL CONTENTS :- Introduction Mechanism of action Structure activity relationship (SAR) Analogous

2. INTRODUCTION Dicoumarol (3,3′-methylene-bis-4-hydroxycoumarin) is a naturally coumarin -based compound which has long been used as an oral anticoagulant drug It is metabolically produced from coumarin which was first isolated from both of the Tonka bean ( Dipteryx odorata ) and the sweet clover ( Melilotus alba and Melilotus officinalis ) It is now known to be present in many other plants. Dicoumarol derivative, warfarin (3-( - acetonyl benzyl)-4-hydroxycoumarin), is commonly used as a natural anticoagulant for the prevention and treatment of excessive blood-clotting disorder Dicoumarol ( INN ) or dicumarol ( USAN ) is a naturally occurring anticoagulant that functions as a functional vitamin K depleter (similar to warfarin , a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases Many dicoumarols and coumarin derivatives have also shown a variety of pharmaceutical activities such as antiinflammatory , antibacterial, antiviral, anticancer, anti-HIV, and antiproliferative properties. Therefore, dicoumarols have received much attention for medical and pharmaceutical applications

3. HISTORY Dicoumarol was isolated by Karl Link 's laboratory at University of Wisconsin, six years after a farmer had brought a dead cow and a milk can full of uncoagulated blood to an agricultural extension station of the university. The cow had died of internal bleeding after eating moldy sweet clover; an outbreak of such deaths had begun in the 1920s during The Great Depression as farmers could not afford to waste hay that had gone bad. Link's work led to the develop of the rat poison warfarin and then to the anticoagulants still in clinical use today .

4. Mechanism of action Like all 4-hydroxycoumarin drugs it is a competitive inhibitor of vitamin K epoxide reductase , an enzyme that recycles vitamin K , thus causing depletion of active vitamin K in blood. This prevents the formation of the active form of prothrombin and several other coagulant enzymes. These compounds are not antagonists of Vitamin K directly—as they are in pharmaceutical uses—but rather promote depletion of vitamin K in bodily tissues allowing vitamin K's mechanism of action as a potent medication for dicoumarol toxicity. The mechanism of action of Vitamin K along with the toxicity of dicoumarol are measured with the prothrombin time (PT) blood test.

5. POISONING Overdose results in serious, sometimes fatal uncontrolled hemorrhage

6. STRUCTURE OF DICOUMAROL

7. STRUCTURE ACTIVITY RELATIONSHIP OF DICOUMAROL Coumarin and its derivatives are principal oral anticoagulants Coumarin is water insoluble, however 4-hydroxy substitution confers weakly acidic properties to the molecule that makes it water soluble under slightly alkaline conditions. The followings are the structures of coumarin and its derivatives (Coumarin,   4-Hydroxycoumarin,   Warfarin and    Dicoumarol) Warfarin is marketed as the sodium salt as racemate , however, The S(-) isomer is about times more potent than the R(+) isomer The minimal requirements for anticoagulant activity are : 4-hydroxy group a 3-substituent a bis molecule. 3-Indanediones The 1,3-indanediones have been known to be anticoagulant since 1940s. A commercially available indandione is anisindione. The molecule has a weakly ionizable proton on C-2 that is extracted in alkaline solutions to confer mildly soluble properties

8. SYNTHESIS OF DICOUMAROL Orally active anticoagulant drugs belong to the chemical categories of coumarins and indanedione derivatives

9. ANALOGOUES OF DICOUMAROL Tromexan or Pelentan (Ethyl biscoumacetate ) : Chemically ethyl- bis (4hydroxycoumarin-3-yl)-acetate, is an analogue of dicoumarol . It is used as oral anticoagulant, and for quicker in action. It can be prepared by condensing 4hydroxycoumarin and glyoxalic acid in the following way

10. Dicoumarol is a natural 4HC derivative and served as the earliest anticoagulant; whereas warfarin, phenprocoumon and acenocoumarol are the most widely prescribed synthetic 4HC anticoagulants. These compounds share the 4HC core structure but differ in substitution at 3-position on the pyrone ring

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