Crystallographic and Docking Characterization of a 4‐(4‐Chlorophenyl) Chromene–1,4‐Dioxane Co‐Crystal

Abstract

Chromene derivatives are known for their diverse biological activities and potential applications in drug discovery. In this study, we present the first crystallographic resolution of 2-amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile co-crystallized with 1,4-dioxane (molecular formula: C22H25ClN2O4, molecular weight: 416.89 g/mol). The compound was unexpectedly obtained during an attempted synthesis of acridine derivatives via a one-pot multicomponent reaction involving 5,5-dimethylcyclohexane-1,3-dione, benzylidene malononitrile, and a primary amine. Instead of the desired acridine structure, a chromene derivative co-crystallized with 1,4-dioxane was formed. Due to its known structural adaptability and potential for polymorphism, this chromene derivative was selected for detailed investigation. Previous studies have demonstrated its ability to crystallize in multiple forms (solvent-free, acetone solvate, and acetic acid cocrystal), making it an ideal model to explore solvent effects on supramolecular assembly and ligand interaction. Single-crystal X-ray diffraction and Hirshfeld surface analysis provided detailed insights into molecular packing and intermolecular interactions. Density functional theory (DFT) calculations were performed to assess the electronic properties and reactivity. Molecular docking studies targeted biologically significant proteins-EAAT1, GSK-3 beta, EGFR, and CA II-under solvent-included and solvent-free conditions to evaluate the influence of 1,4-dioxane. Our results demonstrate that explicit solvent molecules enhance ligand stability within active sites, modulating hydrophobic, and hydrogen bonding interactions. This integrative study highlights the critical role of solvent effects in ligand-protein interactions, offering a structural, and theoretical framework for future pharmacological investigations of chromene derivatives.