Synthesis and structure-activity relationships of novel warfarin derivatives.

摘要: 4-Hydroxycoumarins such as warfarin 1 have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition which produces a deficiency and consequently K-dependent proteins involved in thrombus formation. Using probes, 4-sulfhydrylwarfarin 7 4-chlorowarfarin 10 it shown vitro that VKER by dependent on deprotonation 4-hydroxycoumarin moiety. In addition, nature substituent carbon 3 modulated inhibition. More specifically, linear isoprenyl side chain increased when compared to cyclical substituents present warfarin. An example an natural product ferulenol 19 derived from Ferula communis. Ferulenol confers approximately 22 times more potent than 1.5 rodenticide brodifacoum this assay. Based these data hypothesized bind active site thereby mimicking transition state elimination water substrate 2-hydroxyvitamin K.