Solid-state tautomeric structure and invariom refinement of a novel and potent HIV integrase inhibitor

Acta Crystallogr C. 2013 Mar;69(Pt 3):285-8. doi: 10.1107/S0108270113003806. Epub 2013 Feb 14.

Abstract

The conformation and tautomeric structure of (Z)-4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide, C27H22F3N3O5, in the solid state has been resolved by single-crystal X-ray crystallography. The electron distribution in the molecule was evaluated by refinements with invarioms, aspherical scattering factors by the method of Dittrich et al. [Acta Cryst. (2005), A61, 314-320] that are based on the Hansen-Coppens multipole model [Hansen & Coppens (1978). Acta Cryst. A34, 909-921]. The β-diketo portion of the molecule exists in the enol form. The enol -OH hydrogen forms a strong asymmetric hydrogen bond with the carbonyl O atom on the β-C atom of the chain. Weak intramolecular hydrogen bonds exist between the weakly acidic α-CH hydrogen of the keto-enol group and the pyridinone carbonyl O atom, and also between the hydrazine N-H group and the carbonyl group in the β-position from the hydrazine N-H group. The electrostatic properties of the molecule were derived from the molecular charge density. The molecule is in a lengthened conformation and the rings of the two benzyl groups are nearly orthogonal. Results from a high-field (1)H and (13)C NMR correlation spectroscopy study confirm that the same tautomer exists in solution as in the solid state.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Crystallography, X-Ray
  • Electrons
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology*
  • Hydrogen Bonding
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Molecular Structure
  • Pyridines / chemistry*
  • Pyrrolidines / chemistry*
  • Solutions / chemistry*

Substances

  • (Z)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide
  • HIV Integrase Inhibitors
  • Pyridines
  • Pyrrolidines
  • Solutions