Concise synthesis and preliminary biological evaluation of new triazolylthioacetone derivatives bearing pyridine, pyrazine, and 3,4,5-trimethoxybenzyl fragment

Based on our previous work, a series of novel triazolylthioacetones incorporating pyridine, pyrazine, and 3,4,5-trimethoxybenzyl fragment were synthesized, and evaluated for antiproliferative activities and interactions with tubulin. Some analogues exhibited moderate to excellent potency, with the most promising compound IIc possessing IC₅₀ values of 0.62, 1.46, and 3.65 μM against HT-29, HCT116, and HepG2 tumor cells, respectively, which were comparable with the positive control CA-4. Mechanistical studies revealed that IIc concentration-dependently caused cell cycle arrest at the G₂/M phase in HCT116 tumor cells, and displayed a significant inhibition of tubulin polymerization with an IC₅₀ value of 12.7 μM. Moreover, molecular docking analysis suggested that IIc could occupy the colchicine-binding site in a similar way with typical tubulinpolymerizationinhibitors. These results highlighted the 4-amino-triazolylthioacetone scaffold as potential tubulin polymerization inhibitors for development of highly efficient Anticancer agents.