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

Abstract

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.