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

10. 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

11. 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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