Tuning crystal packing and reactivity through electrostatic and dispersion interactions: The case of phenytoin and its derivatives

Hydantoin derivatives represent a versatile class of heterocycles, known for their pharmacological properties. Because drug efficacy often depends on the fine-tuning of weak intermolecular (non-covalent) interactions, analysis of the crystal structure of a drug molecule is important, as it enables deciphering its interaction profile. In this study, the crystal packing of phenytoin and its selected derivatives were examined through dimeric motifs with different recognition modes using force-field calculations and a density functional theory (DFT) approach. The relatively polar ethoxyacetyl group at the N3 position of the hydantoin ring, capable of forming hydrogen bonds, enhances the contribution of electrostatic and polar components to the total interaction energy. In contrast, the long alkyl chain promotes hydrophobic contacts, leading to dispersion forces dominating over electrostatic interactions. The reactivity of phenytoin and its derivatives were further evaluated by examining the influence of these substituents using conceptual density functional theory (CDFT) descriptors. These findings demonstrate that substituents significantly affect crystal packing and the balance of non-covalent interactions, providing valuable insights for optimizing molecular recognition and drug?target interactions in the design of new therapeutic agents.