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Synthesis, in vivo Anticoagulant Evaluation and Molecular Docking Studies of Bicoumarins Obtained from Furocoumarin Peucedanin

[ Vol. 12 , Issue. 7 ]

Author(s):

Alla V. Lipeeva, Mikhail V. Khvostov, Dmitry S. Baev, Makhmut M. Shakirov, Tatijana G. Tolstikova and Elvira E. Shults   Pages 674 - 683 ( 10 )

Abstract:


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.

Keywords:

Bicoumarins, peucedanin, click reactions, anticoagulant, molecular docking.

Affiliation:

Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, P.O. Box: 630090, Novosibirsk, Russia.

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