“Conformational Simulation” of Sulfamethizole by Molecular Complexation and Insights from Charge Density Analysis: Role of Intramolecular S···O Chalcogen Bonding

Intramolecular
S···O chalcogen bonding and its potential
to lock molecular conformation have been examined in the crystal forms
of sulfamethizole, a sulfonamide antibiotic. Molecular complexes of
sulfamethizole, including salts and cocrystal, have been synthesized,
and their crystal structures were analyzed in order to examine the
possible conformational preferences of the molecule in various ionic
states and supramolecular environments (neutral/cocrystal, anionic
salt, and cationic salt forms). The electrostatic potential mapped
on Hirshfeld surfaces generated for these crystal forms provides insights
into the possible binding modes of the drug in different environments.
Further, the observed conformation locking feature has been rationalized
in terms of the experimental charge density features of the intramolecular
S···O chalcogen bonding in sulfamethizole. The study
quantitatively illustrates and rationalizes an intriguing case of
a local minimum of molecular conformation being exclusively preferred
over the global minimum, as it facilitates more efficient intermolecular
interactions in a supramolecular environment.