Synthesis of 2-Aryl(alkyl)benzimidazole Hydroxamic Acids as HDAC Inhibitors with Anti-Angiogenesis Properties

This study synthesized a series of C2 and N1-substituted benzimidazole hydroxamic acid (6-19) as HDAC inhibitors. Among them, most of 2-aryl(alkyl)benzimidazole hydroxamic acids (11-16) exhibited HDAC6 activity and slight HDAC1 (or HDAC2) activity. In addition, they also showed anti-angiogenic activity and inhibited the growth of tested cancer cells. For instance, compound 13 has a GI₅₀ of 3.9 μM against EPCs and inhibited the growth of HCT-116, SK-Hep-1, and PC-3 cells with GI₅₀ values of 1.3, 4.2, and 7.5 μM, respectively. The exact mechanism underlying the anti-angiogenic effects of these compounds remains unknown, though this study gives an insight into how future HDAC inhibitors that aim to target blood vessel formation can be designed.