New Triazole Hybrids as Anticancer Agents Targeting Thymidylate Synthase: Synthesis, Biological and Molecular Docking Studies

The present work describes the synthesis and antiproliferative activity of new triazole hybrids. The anticancer results showed that the synthesized hybrids were most sensitive toward colon HCT-116 followed by liver HepG2 and breast MCF-7 carcinomas. Among all the hybrids, compound <b>10</b> resulted in remarkable cytotoxicity with IC₅₀ of 1.14 μM, six times higher than reference drug, Doxorubicin (IC₅₀ of 6.96 μM) and also emerged as most potent TS inhibitor with IC₅₀ 0.54 μM. In order to inquire its effect on intracellular mechanism, cell cycle and apoptosis studies were performed. Compound <b>10</b> treated HCT-116 cells caused remarkable increase in cell distribution in G1 phase, however it decreases both S and G2 population with early and late apoptosis. The study was supported by docking study where compound <b>10</b> revealed highest binding affinity and interacted with Arg50, Arg174, Asp218, Cys195, and Ser216, essential for the TS activity. These outcomes suggest that compound <b>10</b> acts as a TS inhibitor and could be promising target for cancer therapy.