Design and synthesis of novel diphenacoum-derived, conformation-restricted vitamin K 2,3-epoxide reductase inhibitors

Two novel diphenacoum-derived analogues 5 and 6 are designed, synthesized and tested as potential vitamin K 2,3-epoxide reductase (VKOR) inhibitors. The inhibition studies indicated that 5 is a potent VKOR inhibitor, which confirmed that the replacement of the tetrahydronaphthalene on diphenacoum to a chroman functionality does not have a major impact on inhibition potency. The conformation-restricted compound 6 is a moderate inhibitor which may serve as a lead compound for further study of the mode of action of coumarin-type anticoagulants at the molecular level.

Graphical abstractEfficient syntheses of two novel diphenacoum-derived, conformation-restricted analogues 5 and 6 are presented. Biological evaluation indicated that 5 is a potent vitamin K 2,3-epoxide reductase inhibitor and 6 is a moderate inhibitor, which may serve as a lead compound for further mode of action studies.Figure optionsDownload full-size imageDownload as PowerPoint slide