Synthesis and Biological Evaluation of Novel 2-Aroyl Benzofuran-Based Hydroxamic Acids as Antimicrotubule Agents.

Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N -hydroxyacrylamide or a N -hydroxypropiolamide at the 5-position of the 2-aroylbenzo[ b ]furan skeleton, to produce compounds 6a - i and 11a - h , respectively. Among the synthesized compounds, derivatives 6a , 6c , 6e , 6g , 11a, and 11c showed excellent antiproliferative activity, with IC 50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a - g , 6i , 11a , 11c , and 11e , although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.