Synthesis, Evaluation and Docking Study of 1, 3, 5-Triazine Derivatives as Cytotoxic Agents against Lung Cancer

Knowing that dihydrofolate reductase (DHFR) is the primary target enzyme for antifolate drugs and 1,3,5-triazine derivatives containing various amino groups at position 2, 4 or 6 have been known as potent anticancer drugs, two series of tri-amino-substituted 1,3,5-triazine derivatives were designed, synthesized and evaluated as cytotoxic agents against non-small cell lung cancer (A549). The first series are N2-(4-phenylthiazol-2-yl)-1,3,5-triazine-2,4,6-triamine analogs and the second series are4-((4,6-Diamino-1,3,5-triazin-2-yl)amino)-4H-1,2,4-triazole-3-thiol analogs. Out of twenty two synthesized compounds there were thirteen compounds showed a higher cytotoxic activity against A549 cell line than methotrexate and four compounds were equipotent to methotrexate. Compounds 8e, 9a, 10e and 11e showed the highest cytotoxic activity with IC50 values of 50,42, 62 and 28 nM respectively. Molecular docking study was performed to interpret the comparative differences in the binding interactions of the synthesized novel compounds at molecular level as inhibitors of human dihydrofolate reductase (hDHFR) and to understand the structure activity relationships. The excellent anticancer activity of synthesized analogs presented in this study needs further investigation as highly promising cytotoxic lead agents against lung cancer.