A synthetic approach towards drug modification: 2-hydroxy-1-naphthaldehyde based imine-zwitterion preparation, single-crystal study, Hirshfeld surface analysis, and computational investigation

The present study focuses on the modification of primary amine–functionalized drugs, namely pyrimethamine and 4-amino-N-(2,3-dihydrothiazol-2-yl)benzenesulfonamide, through a condensation reaction with 2-hydroxy-1-naphthaldehyde in methanol, yielding two new organic zwitterionic compounds: (E)-1-(((4-(N-(2,3-dihydrothiazol-2-yl)sulfamoyl)phenyl)iminio)methyl)naphthalen-2-olate (DSPIN) and (E)-1-(((4-amino-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl)iminio)methyl)naphthalen-2-olate (ACPIN). The crystal structures of both compounds were confirmed as imine-based zwitterionic products by single-crystal X-ray diffraction (SC-XRD), revealing stabilization through various noncovalent interactions. Supramolecular assembly was investigated using Hirshfeld surface analysis, while void analysis was employed to predict the mechanical response of the crystals. Density Functional Theory (DFT) calculations showed good agreement with experimental structural parameters. Frontier molecular orbital (FMO) analysis indicated that the HOMO–LUMO gap of DSPIN is 0.15 eV smaller than that of ACPIN, attributed to HOMO destabilization and LUMO stabilization in DSPIN. Charge distribution analysis suggested the presence of intramolecular hydrogen bonding, as well as intermolecular hydrogen bonds, dipole–dipole, and dispersion interactions.