Synthesis and X-Ray Structural Analyses Combined Anticancer Efficacy and Molecular Docking for N-Aryl-(2-pyridyl)aldimines

The reaction of 2-amino-4,6-dimethylpyridine with 4-cyanobenzaldehyde, salicylaldehyde or 2-hydroxy-1-naphthaldehyde furnished the corresponding N-aryl-(2-pyridyl)aldimines in very good yields. The synthetised Schiff bases were characterized by FT-IR, ¹H, ¹³C, DEPT-135 and [¹H,¹³C]-HSQC NMR spectroscopy, HRMS and elemental analyses. Additionally, the structure of 2-((E)-(4,6-dimethylpyridin-2-ylimino)methyl)phenol was unambiguously determined by single crystal X-ray diffraction analysis. Hirshfeld analysis of molecular packing was performed. The most common intermolecular interaction is the hydrogen-hydrogen (56.8 %) contacts while the most significant interactions are the O…H (6.5 %) and C…C (4.2 %) contacts. DFT calculated geometric parameters and NMR chemical shifts are well correlated with the experimental data. This compound has a net dipole moment of 2.4261 Debye. The MCF-7 growth was suppressed by N-aryl-(2-pyridyl)aldimines more than that for T47D cell line. The IC₅₀ values of 4-((E)-(4,6-dimethylpyridin-2-ylimino)methyl)benzonitrile against MCF-7 and T47D cell lines were the lowest and it is considered the most promising candidate as anticancer agent. Furthermore, this study conducted a molecular docking of benzonitrile-based Schiff base onto DNA duplex to explore a potential molecular mechanism for the robust anticancer activities of this Schiff base adduct. The molecular docking results indicate that benzonitrile-based Schiff base exhibits characteristics of a potential DNA minor groove binder.