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

The current work is about the modification of primary amine functionalized drugs, pyrimethamine and 4-amino-N-(2,3-dihydrothiazol-2-yl)benzenesulfonamide, via condensation reaction with 2-hydroxy-1-naphthaldehyde to produce 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) in methanol as a solvent. The crystal structures of both compounds were confirmed to be imine-based zwitterionic products via single-crystal X-ray diffraction (SC-XRD) analysis which indicated that the stabilization of both crystalline compounds is achieved via various noncovalent interactions. The supramolecular assembly in terms of noncovalent interactions was explored by the Hirshfeld surface analysis. Void analysis was carried out to predict the crystal mechanical response. Compound geometries calculated in the DFT (Density Functional Theory) study showed reasonably good agreement with the experimentally determined structural parameters. Frontier molecular orbital (FMO) analysis showed that the DSPIN HOMO/LUMO gap is by 0.15 eV smaller than the ACPIN HOMO/LUMO gap due to some destabilization of the DSPIN HOMO and some stabilization of its LUMO. The results of the charge analysis implied formation of intramolecular hydrogen bonds and suggested formation of intermolecular hydrogen bonding and dipole-dipole and dispersion interactions.

Preparation, Crystal Structure, Supramolecular Assembly, and DFT Studies of Two Organic Salts Bearing Pyridine and Pyrimidine.

The effective preparation of two new pyrimidine- and pyridine-based organic crystalline salts with substituted acidic moieties (i.e., (Z)-4-(naphthalen-2-ylamino)-4-oxobut-2-enoic acid (DCNO) and 2-hydroxy-3,5-dinitrobenzoic acid (PCNP)) using methanol as a solvent has been reported. These molecular salts have ionic interactions that are responsible for their structural stabilization in their solid-state assemblies. The crystal structures of DCNO and PCNP were determined by the single-crystal X-ray diffraction (SCXRD) technique. The SCXRD study inferred that cations and anions are strongly packed due to N-H···O, N-H···N, and C-H···O noncovalent interactions in DCNO, whereas in PCNP, N-H···N noncovalent interactions are absent. The noncovalent interactions in both organic crystalline salts were comprehensively investigated by Hirshfeld surface analysis. Further, a detailed density functional theory (DFT) study of both compounds was performed. The optimized structures of both compounds supported the existence of the H-bonding and weak dispersion interactions in the synthesized organic crystalline salt structures. Both compounds were shown to have large and noticeably different HOMO/LUMO energy gaps. The atomic charge analysis results supported the SCXRD and HSA results, showing the formation of intermolecular noncovalent interactions in both organic crystalline salts. The results of the natural bond orbital (NBO) analysis confirmed the existence of (relatively weak) noncovalent interactions between the cation and anion moieties of their organic crystalline salts. The global reactivity parameters (GRPs) analysis showed that both organic crystalline salts' compounds should be quite thermodynamically stable and that DCNO should be less reactive than PCNP. For both compounds, the molecular electrostatic potential (MEP) analysis results support the existence of intermolecular electrostatic interactions in their organic crystalline salts.