New Schiff Base Derivative Triazines: Their Synthesis, Molecular Docking Studies, and Anticancer Activities in Human...

Lung cancer has high mortality rates among both men and women worldwide. Nevertheless, mortality rates have been reported to decline with the advancement of novel therapeutic agents and the identification of new molecular targets. Schiff bases and triazine compounds have significant biological activity. For this purpose, new Schiff base derivative triazine compounds (TrzSchf 1-3) were synthesized in our study. The activities of the new compounds, characterized by spectroscopic techniques, against A549 lung cancer and MRC5 normal lung cells were identified in a series of studies. It was observed that TrzSchf 1-3 generally showed a growth-inhibitory effect against lung cancer cells (A549) and a non-toxic effect against normal lung cells (MRC5). Notably, TrzSchf 1 and TrzSchf 2, 3 exhibited prominent cytotoxic effects in A549 cells, with IC₅₀ values of 14.24 and > 50 μM, respectively. It was observed that the compound with the most potent cytotoxicity against lung cancer cells was TrzSchf 1 (Selective Index: 3.62). In A549 cells, an increase in MAPK gene expression was observed for all compounds. It was observed that the expression of Caspase-3, CD40, CHK1, P27, P38, and P53 proapoptotic proteins increased by all compounds (TrzSchf 1-3), whereas the expression of antiapoptotic proteins such as BCL-2 and NFκB decreased by these compounds. The compounds are thought to be potential inhibitors of BCL-2 and NFκB, which are associated with cell death. Complementary and guiding in silico studies supported the experimental findings. BCL-2 was determined as the most favorable molecular target based on docking scores, and e-pharmacophore modeling further revealed key interaction features and enabled SAR analysis. The drug-likeness potential of the TrzSchf derivatives was evaluated based on Lipinski's Rule of Five parameters. Overall, both experimental and computational results suggest that TrzSchf 1-3 are promising lead candidates for further investigation in lung cancer therapy.