Alla V. Lipeeva, Mikhail V. Khvostov, Dmitry S. Baev, Makhmut M. Shakirov, Tatijana G. Tolstikova and Elvira E. Shults Pages 674 - 683 ( 10 )
Background: Synthesis of 7,7 -linked bicoumarins, 3,3 -linked bi(2-isopropyl)psoralens as well as 1H-1,2,3-triazole linked coumarin–2,3-dihydrofurocoumarin and furocoumarin–2,3-dihydrofurocoumarin hybrids was performed by two alternative pathways, either involving a catalyzed transformations of the ethynyl derivatives of plant coumarins – peucedanin or peuruthenicin.
Objective and Methods: The Sonogashira reaction of 7-ethynyl coumarins or 3-ethynyl-2-isopropylpsoralen with the subsequent coumarin triflates led to 7,7´-linked bicoumarins or 3,3´-linked bipsoralens. 1,2,3-Triazole linked coumarin–2,3-dihydrofurocoumarin or furocoumarin–2,3-dihydrofurocoumarin hybrids were synthesized by a regioselective Cu-catalyzed cycloaddition reaction of 2-azidooreoselone with 7-alkynylcoumarins or 3-ethynyl-2-isopropylpsoralen.
Results: Pharmacological screening of synthesized bicoumarins for anticoagulant activity in vivo revealed that coumarin–dihydrofurocoumarin hybrids linked with a 1,2,3-triazole ring 20 and 22 were the most active compounds. The presented prothrombin time (PT) values comparable to the reference drug warfarin in a dose 100 mg/kg. Docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site.
Conclusion: The moderate toxicity of compounds 20 and 22 (LD50 valuewas more than 3000 mg/kg) encouraged the further design of therapeutically relevant analogues based on these novel type of coumarin hybrids.
Bicoumarins, peucedanin, click reactions, anticoagulant, molecular docking.
Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, P.O. Box: 630090, Novosibirsk, Russia.