Synthesis, X‐ray Structure, Hirshfeld and DFT Combined Anticancer Efficiency, DNA‐binding, and Molecular Docking for (E)‐di‐Aryl‐Aldimines

The synthesis, characterization, Hirshfeld, DFT, anticancer properties and molecular docking of di‐aryl‐aldimines 1 – 4 are presented. Schiff bases 1 – 4 were synthesized by reaction of aromatic aldehydes ArCHO (Ar = 1‐pyrenyl; 2‐hydroxyphenyl; 1‐naphthalenyl or 4‐cyanophenyl) with 1‐aminonaphthalene, respectively. The structure of 4 was determined by single crystal X‐ray. Hirshfeld calculations were carried out to analyze the molecular packing of 4 . The most dominant noncovalent interactions were the H⋯H (35.0%) and C⋯H (39.6%) contacts. DFT calculations on the studied systems were performed to predict and compare their electronic properties. Both aromatic rings were twisted from each other by 49.6°, 41.77°, 47.58°, and 42.94° for compounds 1 , 2 , 3 and 4 , respectively, where the bulkiest ring was found in 1 . The calculated dipole moments were 1.7864, 2.0305, 1.6020 and 4.6294 eV for 1 , 2 , 3 and 4 , respectively; hence, 4 is the most polar one. Compound 2 has the highest HOMO‐LUMO energy gap of 3.778 eV as it has the least conjugated system. Compound 2 has the highest binding possibly due to the presence of phenolic group which is capable to form hydrogen bonding with DNA bases or backbone phosphates. IC 50 values of 50, 56, and 60.75 µg/mL against HepG2 and 89, 91, and 124 µg/mL against HCT116 were obtained for compounds 2 , 3 and 4 , respectively. The selective index of compounds 1 – 4 was calculated and it indicated that compound 4 exhibits enhanced safety and selectivity compared to cisplatin . Molecular docking studies demonstrated that the tested compounds 1 – 4 exhibited excellent binding affinities toward EGFR.