Tautomerism of Warfarin: Combined Chemoinformatics, Quantum Chemical, and NMR Investigation.
J Org Chem
; 80(20): 9900-9, 2015 Oct 16.
Article
en En
| MEDLINE
| ID: mdl-26372257
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Teoría Cuántica
/
Warfarina
/
Simulación de Dinámica Molecular
/
Anticoagulantes
Idioma:
En
Revista:
J Org Chem
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos