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 (<b>9</b>-<b>29</b>) are described herein. Among these compounds, 6-arylpyridines (<b>13</b>-<b>23</b>) 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 <b>25</b>, <b>27,</b> and <b>29</b> bearing benzo[d]imidazole and benzo[d]oxazole side chains displayed more broad-spectrum antitumor activities against all tested cancer cell lines. <b>29</b> 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 <b>29</b> displays strong tubulin polymerization inhibitory activity (IC<sub>50</sub> = 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.