Relationship between structure and anticoagulant activity of coumarin derivatives

Thirty-five coumarin derivatives have been examined for their anticoagulant activity in rabbits by determining the prothrombin time by a modification of Quick's onestage method, in order to find out the structural features eliciting the activity. The compounds include methoxylated dicoumarols, substituted 4-hydroxycoumarins, coumarins devoid of a 4-hydroxyl group, such as 3- and 4-phenylcoumarins and 4-methylcoumarins, and some complex coumarin derivatives having additional rings. The results show the complexity of the problem and the involvement of various factors. Among these the importance of molecular geometry is emphasized by the high activity of calophyllolide (31) and a new synthetic compound, 4-methyl-2,5-dioxo-3-phenyl-2H,5H-pyrano[3,2-c][1]-benzopyran (30). The importance for the anticoagulant activity of a substituent in position 8 of the coumarin moiety, and the role of ability to ionize with regard to the vitamin-K-like property of some hydroxylated phenylcoumarins, are also indicated.