Anticoagulant rodenticides 4-hydroxycoumarins

Rengel I, Friedrich A (1993) Detection of anticoagulant rodenticides (4-hydroxycoumarins) by thin-layer chromatography and reversed-phase high performance liquid chromatography with fluorescence detection. Vet Res Comm 17 421-427... 

Fergusson, D. (1994). The effects of 4-hydroxycoumarin Anticoagulant Rodenticides on Birds and the Development of Techniques for Non-destructively Monitoring Their Ecological Effects, Ph.D. Thesis, University of Reading, UK. 

Felice, L.J., Chalermchaikit, T., Murphy, M.J. (1991). Multi-component determination of 4-hydroxycoumarin anticoagulant rodenticides in blood serum by liquid chromatography with fluorescence detection. J. Anal. Toxicol. 15(3) 126-9. 

The first anticoagulant rodenticide was dicoumarin (19). Its anticoagulant effect was first observed on cattle. Coumarin has an odour reminiscent of hay. When mown sweet clover (Melilotus albe) becomes mouldy, dicoumarin is formed from coumarin, and cattle fed with such mouldy, sweet clover hay bleed to deat when injured because of reduced blood coagulation (Campbell and Link, 1941 Stahmann et al., 1941). Dicoumarin, 3,3 -methylene-bis(4-hydroxycoumarin), is obtained by the condensation of 2 moles of 4-hydroxycoumarin (20) and 1 mole of formaldehyde in aqueous solution. 

The best known and most widely used anticoagulant rodenticide is 3-(l-phenyl-2-acetylethyl)-4-hydroxycoumarin, (warfarin, 21). It is synthesised from 4-hydroxycoumarin (22) by Michael addition with 1 -phenyl-3-oxobutene-1 as the reagent (23) (Ikawa et al, 1944). 

As a result of intensive research, derivatives of 4-hydroxycoumarin were found, which proved to be particularly efficient against rodents and resistant to anticoagulant rodenticides. Difenacoum (34) is a chronic rodenticide, which acts as a typical indirect blood anticoagulant similar to warfarin. However, it is effective against rats and mice, which are resistant to warfarin and other anticoagulant rodenticides, and is more toxic than warfarin to susceptible strains of these rodents. The chemical composition of difenacoum is 3-(3-p-biphenyl-1,2,3,4-tetrahydro-naphth-l-yI)-4-hydroxycoumarin. Its acute oral LD50 is 1.8 mg/kg for Norway rats (Hadler et al., 1975a,b). 

Brodifacoum [3-(3-(4 -bromobiphenyl-4-yl)-l,2,3,4-tetrahydro naphth-l-yl)-4-hydroxycoumarin] is one of the newer and more potent second-generation anticoagulant rodenticides. It was first introduced in 1977 by Sorex Ltd. of London, and then developed by the Imperial Chemicals Incorporated (ICI) Plant Protection Division (Chalermchaikit et al., 1993). 

Warfarin [81-81-2] (6) is prepared by the Michael condensation of benzyHdene acetone with 4-hydroxycoumarin (86). It is used as a rodenticide (see Poisons, commercial) and in anticoagulant therapy. 

The bis(hydroxycoumarin) derivative dicoumarol (45), which was first identified as the causative agent of sweet clover disease in cattle, is used as an anticoagulant in the treatment of thrombosis. Similar compounds with other linking groups have been used, and warfarin (46), which was first introduced as a rodenticide, is also of value. The hydroxycoumarins interfere with the function of vitamin K in the synthesis of prothrombin and other blood... 

This group of compounds have a 4-hydroxycoumarin ring with different side-chain substituents at the 3-position. Commonly used superwarfarin anticoagulant rodentieides in this group are bromadiolone, brodifacoum, coumate-tralyl, coumafuryl, and difenacoum. Brodifacoum, difena-coum and bromadiolone are three of the most commonly used rodentieides around the world. Brodifacoum is the most frequently used rodenticide in the USA. These rodentieides share most of their physical and chemical characteristics, as well as their toxicokinetics, toxicody-namics, and mechanism of toxicity, and the medical toxicological management is the same for all superwarfarins. 

An even more important derivative is 3-[3-(4 -bromobiphenyl-4-yl)-1,2,3,4-tetrahydronaphth-l-yl]-4-hydroxycoumarin (brodifacoum, 35). This anticoagulant of exceptional potency is capable of control resistant rodents as well as several noncommensal species. Contrary to first generation anticoagulants, a bait concentration of only SO mg/kg brodifacoum is adequate to give control even in a single feeding for most species. As with other anticoagulants, vitamin K, is an effective antidote. In contrast with other acute rodenticides, symptoms are delayed and no bait shyness is observed (Dubock and Kaukeinen, 1978). Its effectiveness... 

In fermenting hay, o-coumaric acid (8) is converted into dicoumarol [3,3 -methylenebis(4-hydroxycoumarin)] (13), a compound with marked anticoagulant properties (Beilis et al., 1967 Davies and Ashton, 1964), that occasionally has been responsible for the death of livestock (Sneader, 1985). The synthesis of warfarin (14), a powerful rodenticide, was based on these properties, and for a time, this compound was effective in controlling populations of rats. Recently, however, a strain of super rats has emerged which have developed an enzyme system that allows them to cope with this warfarin (Mann, 1987 Sneader, 1985). Regular low doses of warfarin can prevent strokes in humans (Singer, 1990). 

Several 3-hydroxyarylmethyl-4-hydroxycoumarins were also found to be useful blood anticoagulants and rodenticides. Representative derivatives are given (74, 75). 

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