Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

Mimicking different pharmacophoric units into one scaffold is a promising structural modification tool to design new drugs with enhanced biological properties. To continue our research on the tubulin inhibitors, the synthesis and biological evaluation of arylpyridine derivatives (9–29) are described herein. Among these compounds, 6-arylpyridines (13–23) bearing benzo­[d]­imidazole side chains at the 2-position of pyridine ring displayed selective antiproliferative activities against HT-29 cells. More interestingly, 2-trimethoxyphenylpyridines 25, 27, and 29 bearing benzo­[d]­imidazole and benzo­[d]­oxazole side chains displayed more broad-spectrum antitumor activities against all tested cancer cell lines. 29 bearing a 6-methoxybenzo­[d]­oxazole group exhibited comparable activities against A549 and U251 cells to combretastatin A-4 (CA-4) and lower cytotoxicities than CA-4 and 5-Fu. Further investigations revealed 29 displays strong tubulin polymerization inhibitory activity (IC50 = 2.1 μM) and effectively binds at the colchicine binding site and arrests the cell cycle of A549 in the G2/M phase by disrupting the microtubules network.