New 1,2,3-Triazole Hybrids as Anticancer Agents: Design, Synthesis, Characterization, and In Silico Studies

Two series of 1,2,3-triazole-based molecules were synthesized. Their physical properties were documented, and cytotoxicity was evaluated against normal lymphocytes, leukemic, adherent, and nontumor cell lines. Compounds 11, 15, and 16 were inactive, while compound 17 affected both normal and cancer cells. Compounds 18 and 20 showed activity against BJ and A549 cell lines, with compound 20 being selective for T-cell leukemias and compound 18 moderately affecting B-cell leukemia. Compound 12 specifically affected the HCTp53 KO cell line, while compounds 13 and 14 were selective for U2O2 and HCT116 cell lines, respectively. Compound 14 was highly specific for T-cell leukemia, whereas compound 19 was specific for A549 and moderately specific for B-cell lines. Compound 22 affected all tumor cell lines except A549. The active compound induces apoptosis since it activates caspase 3. Spheroid testing revealed that compounds 13 and 22 specifically affected HCT116 spheroids, while compound 19 affected A549 spheroids. Both in vitro and computational analyses demonstrated that compounds 11, 12, and 13 exhibit high affinity for the A Cα subunit of protein kinase A. This suggests a kinase-targeted mechanism of action, providing a structural foundation for future design strategies to optimize the potency of these lead compounds.