Microwave-assisted efficient synthesis of 2-hydroxydeoxybenzoins from the alkali degradation of readily prepared 3-aryl-4-hydroxycoumarins in water.
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This paper describes an operationally simple, green and efficient approach for the synthesis of 2-hydroxydeoxybenzoins bearing diverse substituents from the microwave-assisted alkali degradation of 3-aryl-4-hydroxycoumarins in water. The latter compounds were readily prepared from the intramolecular Claisen condensation reaction of methyl 2-(2-arylacetoxy)benzoates in the presence of Cs2CO3-acetone, in excellent yields and without laborious workup procedures. This method is highly atom-economic and thus applicable for the large-scale synthesis of 2-hydroxydeoxybenzoins. (+info)
Structure-activity relationships of 3,3'-phenylmethylene-bis-4-hydroxycoumarins: selective and potent inhibitors of gram-positive bacteria.
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Vitamin K antagonism of coumarin anticoagulation. A dehydrogenase pathway in rat liver is responsible for the antagonistic effect.
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In the liver, it appears that there are two different pathways for vitamin K reduction. One pathway is irreversibly inhibited by coumarin anticoagulant drugs. The other pathway has been shown in the present study to be composed of enzymes that are not effected by physiological 'in vivo' concentrations of these drugs. This pathway appears to be responsible for the antidotal effect of vitamin K in overcoming coumarin poisoning. In rat liver the pathway has been shown to be composed of DT-diaphorase (EC.1.6.99.2) and a microsomal dehydrogenase(s). The activity of the microsomal dehydrogenase(s) was 3.6-fold higher with NADH than with NADPH present in the test system. It appears that this enzyme is the physiologically important enzyme in the pathway. In contrast with DT-diaphorase, this enzyme(s) is shown to be tightly associated with the mirosomal membrane. The enzyme(s) is not identical with either of the quinone-reducing enzymes cytochrome P-450 reductase or cytochrome-b5 reductase. Our data thus postulate the existence of an as-yet-unidentified microsomal dehydrogenase that appears to have an important function in the pathway. (+info)
An investigation of the pharmacological response to vitamin K1 in the rabbit.
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1. The relationship between pharmacological response and disposition of a dose of vitamin K1 (10 mgkg-1, i.v.) in normal rabbits and in rabbits treated with the coumarin anticoagulant brodifacoum, has been studied. 2. High performance liquid chromatography (h.p.l.c.) with electrochemical detection (EC) was used to determine concentrations of vitamin K1 in plasma, whole liver homogenate, and liver microsomes. 3. After intravenous administration of vitamin K1, plasma concentrations of the vitamin declined in a tri-exponential fashion. There were no differences between the two groups over the first 24 h of the experiment. However, between 24 h and the end of the study, plasma concentrations of vitamin K1 in the presence of brodifacoum were significantly (P less than or equal to 0.05) below those of vehicle-treated rabbits. 4. Seventy-two hours after administration of vitamin K1, plasma concentrations of the vitamin were not different from normal. 5. Three hours after administration of vitamin K1, the concentrations of the vitamin in whole liver were 46.6 +/- 4.3 micrograms g-1 in the presence of brodifacoum, and 32.8 +/- 6.4 micrograms g-1 in the absence of brodifacoum; and were significantly (P less than or equal to 0.05) greater than normal (127.7 +/- 44.3 ng g-1). Likewise, microsomal concentrations of vitamin K1 (4.00 +/- 2.38 micrograms mg-1 protein, and 2.65 +/- 1.01 micrograms mg-1 protein, in the presence and absence of brodifacoum, respectively) were significantly (P less than or equal to 0.01) greater than normal (16.0 +/- 3.5 ng mg-1 protein). 6 In conclusion, there appears to be no direct effect of coumarins on clearance of vitamin K1 from either plasma or liver; the need for large doses of vitamin K1 during coumarin poisoning is due to a greatly increased requirement for the vitamin. (+info)
Vitamin K 2,3-epoxide reductase: the basis for stereoselectivity of 4-hydroxycoumarin anticoagulant activity.
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1. The administration of S-warfarin (1 mg kg-1 i.v.) to rats that were pre-loaded 48 h before with tracer doses (6 micrograms) of 14C-labelled R- or S-warfarin caused the plasma levels of these compounds to increase. This is due to the substitution of the microsomal (vitamin K 2,3-epoxide (K0) reductase) bound R- or S-[14C]-warfarin by the unlabelled 4-hydroxycoumarin administered. The rate of reappearance was 3-4 fold higher for R- than for S-warfarin; t1/2 of release: 1.2 +/- 0.04 and 3.7 +/- 0.6 h, respectively. 2. Liver microsomes prepared from rats pretreated with R- or S-[14C]-warfarin, released these compounds only in the presence of dithiothreitol (DTT; 10 mM). The rate of release was higher for R- than for S-warfarin-treated microsomes. 3. Liver microsomes treated in vitro with R- or S-acenocoumarol could be reactivated by DTT (10 mM). Reactivation was higher for the R- than for the S-acenocoumarol-treated microsomes. 4. The microsomal vitamin K0 reductase activity under 'normal' assay conditions ([DTT] = 2 mM) was as sensitive for R- as for S-4-hydroxycoumarins. At elevated DTT concentrations (= 42 mM) the rate of vitamin K0 conversion was about 1.5 fold higher in the presence of the R-isomers than in the presence of the S-isomers. For instance, at 2 mM DDT the reductase activities in the presence of 2.6 microM R- and S-warfarin were about 15% of control. At 42 mM DTT the activities were 90 and 65% of control, respectively. 5. In the in vitro experiments acenocoumarol appeared to be more potent than warfarin and phenprocoumon. 6. The following mechanism is proposed: vitamin K0 reductase becomes oxidized during substrate reduction. The oxidized (i.e. inactive) form binds equally to the R- and S-enantiomers of 4- hydroxycoumarins. The attached (covalently bound?) coumarin is released by the reactivation (i.e. reduction) of the enzyme. However, the rate of reactivation is strongly attenuated by the attached coumarin. This effect is more pronounced for the S-configuration of the 4-hydroxycoumarin anticoagulants. (+info)
Field trials of flocoumafen against warfarin-resistant infestations of the Norway rat (Rattus norvegicus Berk.).
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The anticoagulant rodenticide flocoumafen was tested against warfarin-resistant Norway rats (Rattus norvegicus Berk.) infesting farm buildings. Complete control was obtained in 10-21 days (mean 14.2 days) in six treatments in which baits poisoned with 0.005% flocoumafen were maintained, in surplus, until rats ceased to feed from them. A further six treatments, in which the application of poisoned bait was restricted to periodic placements of 50 g, were also completely successful in 15-30 days (mean 21.0 days). Less poisoned bait was used in the restricted flocoumafen treatments than in the unrestricted treatments but the time taken to control the rat infestations was significantly longer. (+info)
The susceptibility of Rattus rattus and Bandicota bengalensis to a new anticoagulant rodenticide, flocoumafen.
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The anticoagulant rodenticide flocoumafen was evaluated against Rattus rattus and Bandicota bengalensis. In no-choice 24 h feeding tests 100% mortality occurred at 0.00125% concentration of the poison in the bait in the case of B. bengalensis and at 0.00375% in R. rattus. Feeding of 0.0025% poison bait in 1-day, no-choice and 2-day choice tests resulted in 60% and 75% mortality of R. rattus, respectively, and 100% of B. bengalensis. The differences between the consumption of plain food in the pretreatment period and of poison bait in no-choice tests were non-significant, except in one case. The rodents consumed significantly more (P less than 0.01) poison bait than the plain alternative in the choice trials. Median period of survival and its 95% confidence limits of R. rattus and B. bengalensis, at the 100% mortality dose levels of the poison, were 6.3 (5.04-7.88) and 6.2 (4.92-7.81) days respectively. (+info)
Pen and field trials of a new anticoagulant rodenticide flocoumafen against the house mouse (Mus musculus L.).
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The efficacy of flocoumafen, a novel anticoagulant rodenticide, was evaluated in feeding tests on confined and free-living populations of house mice (Mus musculus L.). In four pen trials, family groups of laboratory-reared wild mice were conditioned to feeding on plain foods and then offered flocoumafen at 0.005% in pinhead oatmeal bait. All 68 mice, comprising juvenile and adult animals, died within 10 days. Ten field trials were carried out, using the same formulated poison bait, against mice infesting farm buildings. Mean treatment success, estimated from live-capture and mortality data, ranged between 87.1 and 100%. The performance of flocoumafen is compared with that of difenacoum, bromadiolone and brodifacoum used at the same concentration in oatmeal bait. Flocoumafen gave an equally effective but quicker kill of mice. It is concluded that flocoumafen is a promising new rodenticide for the control of M. musculus. (+info)