Conformational polymorphism in sulfonylurea drugs: electronic structure analysis.

Area of Science:

• Computational chemistry
• Molecular modeling
• Medicinal chemistry

Background:

• Sulfonylureas are a class of compounds with significant pharmaceutical applications.
• Understanding their conformational and tautomeric preferences is crucial for drug design and development.
• Previous studies have primarily focused on specific conformers and largely overlooked tautomeric forms.

Purpose of the Study:

• To investigate the conformational and tautomeric preferences of a model sulfonylurea using quantum chemical calculations.
• To identify the most stable conformers and assess the accessibility of iminol tautomeric forms.
• To correlate computational findings with known crystal structures of sulfonylurea drugs.

Main Methods:

• High-level quantum chemical calculations including Hartree-Fock (HF), B3LYP, and Møller-Plesset perturbation theory (MP2) methods.
• Analysis of potential energy surfaces to determine conformational and tautomeric minima.
• Gas-phase and solvent-phase calculations to evaluate the influence of the environment.
• Comparison of calculated structures with experimental data from crystal structures.

Main Results:

• A previously unconsidered conformer (SLU-1) featuring an intramolecular hydrogen bond was found to be more stable than the commonly accepted conformer (SLU-2) by approximately 4 kcal/mol in the gas phase.
• The energy difference between these conformers diminished in the solvent phase.
• Iminol tautomeric forms, not previously studied, were found to be energetically accessible (5-6 kcal/mol higher than the most stable form).
• Calculations on dimeric structures showed correlations with known polymorphic crystal structures of sulfonylurea drugs.

Conclusions:

• The SLU-1 conformer represents a more stable and relevant structure for sulfonylureas than previously assumed.
• Tautomeric forms of sulfonylureas are readily accessible and likely play a role in their solid-state properties.
• These findings provide valuable insights for the rational design and understanding of sulfonylurea-based therapeutics, particularly concerning their polymorphism.