title: Tautomerism of Warfarin: Combined Chemoinformatics, Quantum Chemical, and NMR Investigation.
abstract: Warfarin, an important anticoagulant drug, can exist in solution in 40 distinct tautomeric forms through both prototropic tautomerism and ring-chain tautomerism. We have investigated all warfarin tautomers with computational and NMR approaches. Relative energies calculated at the B3LYP/6-311G++(d,p) level of theory indicate that the 4-hydroxycoumarin cyclic hemiketal tautomer is the most stable tautomer in aqueous solution, followed by the 4-hydroxycoumarin open-chain tautomer. This is in agreement with our NMR experiments where the spectral assignments indicate that warfarin exists mainly as a mixture of cyclic hemiketal diastereomers, with an open-chain tautomer as a minor component. We present a diagram of the interconversion of warfarin created taking into account the calculated equilibrium constants (pK(T)) for all tautomeric reactions. These findings help with gaining further understanding of proton transfer and ring closure tautomerization processes. We also discuss the results in the context of chemoinformatics rules for handling tautomerism.
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21702, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Guasch
authors.affiliation: Basic Science Program, Chemical Biology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21702, United States.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Nicklaus
mesh_terms: D000925:Anticoagulants / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011789:Quantum Theory; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry*
chemical_list: D000925:Anticoagulants; D014859:Warfarin