Using small molecule crystal structure data to obtain information about sulfonamide conformation.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Sulfonamide-containing drugs, or sulfa drugs, are widely used for their antibacterial properties.
• Understanding the three-dimensional structures (conformations) of the sulfonamide group is key to elucidating their biological activity.
• Previous computational studies have shown discrepancies in predicting the solid-state conformations of sulfonamides.

Purpose of the Study:

• To investigate the preferred conformations of the sulfonamide group in the solid state.
• To compare experimental solid-state conformations with predictions from high-level ab initio calculations.
• To analyze the influence of the sulfonamide group on adjacent molecular structures.

Main Methods:

• Utilized cluster analysis on crystallographic data from the Cambridge Structural Database (CSD).
• Estimated relative energies of observed sulfonamide conformations in the solid state.
• Extended conformational analysis to adjacent torsion angles.

Main Results:

• Confirmed that many high-level ab initio calculations do not accurately reproduce observed solid-state sulfonamide structures.
• Demonstrated that the sulfonamide group significantly influences the conformations of adjacent torsion angles.
• Provided energy estimations for various observed solid-state forms using CSD data.

Conclusions:

• Experimental data from the CSD is essential for accurately characterizing sulfonamide conformations.
• Computational methods require refinement to reliably predict solid-state drug structures.
• The sulfonamide moiety plays a critical role in dictating the overall molecular shape and interactions of sulfa drugs.