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Analgesic, Anti-Inflammatory, Antipyretic, and Anesthetic Drugs: Dealing With Pain, Inflammation, and Fever
Published in Richard J. Sundberg, The Chemical Century, 2017
In 1933, a Wisconsin dairy farmer brought a dead heifer to the University of Wisconsin. Finding the State Veterinarian’s office closed for the weekend, he went to the biochemistry department. His herd was suffering from severe fatal hemorrhaging. Prof. Karl Link and a graduate student, Eugen Schoeffel, recognized the cause as “sweet clover disease” and, as was characteristic of the condition, the animal’s blood would not clot. The two began to investigate the connection between hemorrhage and spoiled sweet clover hay, the immediate cause of the condition. Link and H. A. Campbell discovered that the condition could be improved with alfalfa extract, which contains vitamin K that promotes blood clotting (see Section 10.1.1.9). In 1939, they solved the second part of the puzzle when they isolated dicoumarol from the spoiled hay. Dicoumarol is a potent anticoagulant. Dicoumarol is metabolized to salicylic acid and Link suspected that the latter might be the active compound. He went on to show that high doses of aspirin did have an anticoagulant effect and suggested that hemorrhage might be a harmful side effect of aspirin. Link also pursued research on synthetic analogs of dicourmarol. From this work came warfarin, which was first used as a rodent poison and then as an anticoagulant in humans.4
A facile and practical p-toluenesulfonic acid catalyzed route to dicoumarols and their biological evaluation
Published in Green Chemistry Letters and Reviews, 2023
Sadeq M. Al-Hazmy, Donia Bensalah, Najet Aouled Dlala, Younes Bouazizi, Houcine Ghalla, Naceur Hamdi
The chemistry of oxygenated heterocycles has been the subject of increasing interest. Coumarins are benzo-fused heterocycles containing oxygen atoms and their synthesis is important because of their widespread occurrence in nature (1–3). Coumarin is a fundamental unit of some biological and pharmaceutical products such as warfarin [4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one], acenocoumarol {4-hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one}, dicoumarol (3,3'-methylenebis[4-hydroxy-2H-1-benzopyran-2-one]), and phenprocoumon [4-hydroxy-3-(1-phenylpropyl)-2H-1-benzopyran-2-one] (4,5). Through metabolization of coumarin in the sweet clover by molds such as Penicillium nigricans and Penicillium jensi, dicoumarols has resulted. Dicoumarols as a natural anticoagulant drug have been extensively studied because of their application in the pharmaceutical industry (6). Some synthetic strategies have been reported for dicoumarols including the total synthesis starting from salicylaldehyde and formaldehyde (7), biosynthesis of dicoumarols employing micro-organisms such as Penicillium jenseni (8), and Knoevenagel condensation of 4-hydroxycoumarins with carbonyls using several catalysts (9–12).