title: Synthesis, in vivo Anticoagulant Evaluation and Molecular Docking Studies of Bicoumarins Obtained from Furocoumarin Peucedanin.
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
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Alla V
authors.initials: AV
authors.lastname: Lipeeva
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Khvostov
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Baev
authors.forename: Makhmut M
authors.initials: MM
authors.lastname: Shakirov
authors.forename: Tatijana G
authors.initials: TG
authors.lastname: Tolstikova
authors.affiliation: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, P.O. Box: 630090, Novosibirsk, Russia. schultz@nioch.nsc.ru.
authors.forename: Elvira E
authors.initials: EE
authors.lastname: Shults
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D003374:Coumarins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D011564:Furocoumarins / Q000737:chemistry; D006860:Hydrogen Bonding; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011517:Prothrombin Time; D051381:Rats; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D003374:Coumarins; D065427:Factor Xa Inhibitors; D011564:Furocoumarins; D014859:Warfarin; D015951:Factor Xa; C587828:peucedanin