Design, Synthesis and Anticancer Evaluation of 4 H ‐Pyrido1,2‐ a pyrimidine‐4‐one‐1,3,5‐triazine Derivatives

ABSTRACT Twenty 4 H ‐pyrido1,2‐ a pyrimidin‐4‐one‐1,3,5‐triazine derivatives were synthesized via cyclization condensation and nucleophilic substitution reactions. The structures of the synthesized compounds were characterized by 1 H NMR, 13 C NMR, IR, and HR‐MS ansalyses. Further structural insights into compound 6d (2‐((4‐chloro‐6‐(dibutylamino)‐1,3,5‐triazin‐2‐yl)oxy)‐7‐fluoro‐4 H ‐pyrido1,2‐ a pyrimidin‐4‐one) were obtained through single‐crystal x‐ray diffraction analysis. The single‐crystal analysis determined that compound 6d belongs to the monoclinic crystal system and adopts the space group P 2 1 / c . The antiproliferative activities of these compounds against breast cancer cells (MDA‐MB‐231), pancreatic cancer cells (panc‐1), and cervical cancer cells (HeLa) were evaluated using the CCK‐8 assay. Most of the 4 H ‐pyrido1,2‐ a pyrimidin‐4‐one‐1,3,5‐triazine derivatives exhibited good anticancer activities. Compound 6m (2‐((4‐chloro‐6‐(cyclohexyl(methyl)amino)‐1,3,5‐triazin‐2‐yl)oxy)‐7‐fluoro‐4 H ‐pyrido1,2‐ a pyrimidin‐4‐one) exhibited the most potent inhibitory effect on the proliferation of MDA‐MB‐231 cells (IC 50 = 6.82 ± 0.03 µM), which was better than that of 5‐fluorouracil (IC 50 = 21.83 ± 0.18 µM). Further studies have shown that compound 6m also strongly inhibits the migration, invasion, and adhesion of MDA‐MB‐231 cells. Molecular docking studies indicate that 6m can interact with phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha isoform (PI3Kα). ADME and toxicity analyses further suggest that these compounds exhibit drug‐like properties. Therefore, compound 6m is a promising lead candidate for developing breast cancer therapeutics.