X-Ray Crystallography, Hirshfeld Surface Analysis, and Molecular Docking Studies of Two Sulfonamide Derivatives

This work reports the crystallographic study of two benzenesulfonamides, 1 ((E)-N-benzyl-3-((benzylimino)methyl)-4-hydroxybenzenesulfonamide) and 2 (N-benzyl-3-(3-(N-benzylsulfamoyl)-2-oxo-2H-chromene-6-sulfonamide). These compounds share structural features with belinostat, an FDA-approved histone deacetylase (HDAC) inhibitor used in the treatment of peripheral T-cell lymphoma. Compound 1 contains one sulfonamide group, meanwhile compound 2 contains two sulfonamide moieties and presents four independent molecules in its unit cell. The crystal packing of 1 and 2 is mainly governed by N–H···O=S hydrogen bonding interactions. π → π* and n → π* stacking interactions also contribute to the molecular assembly. Hirshfeld surface (HS) analysis was carried out to further examine the intermolecular interactions of compounds 1 and 2, revealing that N–H∙∙∙O and C–H∙∙∙O hydrogen bonding interactions, along with O∙∙∙H/H∙∙∙O interactions, are the strongest contributors to the individual surfaces. Interaction energy analysis was also performed to evaluate the relative strength and nature of the intermolecular contacts. Additionally, molecular docking studies of compounds 1 and 2 were performed on the crystal structure of the enzyme HDAC2, an enzyme overexpressed in several cancers, particularly breast cancer. The results revealed that both compounds exhibit a binding mode and binding energies similar to those of belinostat, suggesting their potential as novel therapeutic agents.