4-Hydroxycoumarins

4-Hydroxycoumarins are a class of

aromatic

substituent at the 3-position (the ring-carbon between the hydroxyl and the carbonyl). The large 3-position substituent is required for anticoagulant activity.

The primary mechanism of the 4-hydroxycoumarin drugs is the inhibition of vitamin K epoxide reductase. These compounds are not direct antagonists (in the pharmaceutical sense) of vitamin K, but rather act to deplete reduced vitamin K in tissues. For this reason vitamin K antagonizes their effect, and this has led to the loose terminology of "vitamin K antagonist".

Origin

Although 4-hydroxycoumarin itself is not an anticoagulant, it is an important fungal metabolite from the precursor

sweet clover and is considered a natural mycotoxin substance of combined plant and fungal origin.^[1]

The identification of dicoumarol in 1940 was the precursor to development of the 4-hydroxycoumarin class of drugs.

Effects

The synthetic drugs in the 4-hydroxycoumarin class are all noted primarily for their use as

clotting factors, and certain other metabolic processes involving the binding of calcium

ion.

Drugs and poisons in the class

The simplest synthetic molecule in the 4-hydroxycoumarin class is

half-lives in the body to be greatly increased (sometimes to months). The rodenticide chemicals are sometimes incorrectly referred to as "coumadins" rather than 4-hydroxycoumarins ("Coumadin" is a brand name for warfarin). They are also referred to as "coumarins," in reference to their derivation, although this term also may be deceptive since coumarin

itself, as noted, is not active in clotting, and is used mostly as a perfumery agent.

Pharmaceutical examples of 4-hydroxycoumarin pharmaceuticals include:

Compounds in this class have also been used as pesticides, specifically rodenticides. They act by causing the affected animal to hemorrhage, causing it to seek water, and thus leave dwellings to die outdoors.

The second-generation vitamin K antagonist agents, used only in this fashion as poisons (because their duration of action is too long to be used as pharmaceuticals) include:

Structures


Coumarin This molecule does not affect coagulation	tobacco additive coumarin.	Dicumarol This molecule was the first discovered 4-hydroxycoumarin anticoagulant. It is a dimer type structure connected at the 3 ring position.

Phenprocoumon (anticoagulant)	Warfarin Most commonly used anticoagulant pharmaceutical	Acenocoumarol (anticoagulant)

Tecarfarin (experimental anticoagulant)


Brodifacoum This molecule is a second-generation anticoagulant with a large 3-position substituent which causes it to be retained in fatty tissues for longer times than first-generation compounds and pharmaceuticals. (rodenticide)	Bromadiolone (rodenticide)

Coumatetralyl (rodenticide)	Difenacoum (rodenticide)

Flocoumafen (rodenticide)

References

^ Bye, A., King, H. K., 1970. The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius. Biochemical Journal 117, 237-245.

External links

4-hydroxycoumarins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Synthesis

[1] Bye, A., King, H. K., 1970. The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius. Biochemical Journal 117, 237-245.

[1]