HDAC inhibition is emerging as a new strategy for cancer therapy. We previously reported that Nhydroxy- 3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (9) demonstrated potent histone deacetylases (HDAC) inhibition and anti-inflammatory effects. This continuous study provides detailed structureactivity relationship (SAR) of novel indol-3-ethylsulfamoylphenylacrylamides as anti-cancer agents. These compounds are endowed with potent HDAC inhibitory activity, almost 2.5 folds to 42 folds better than suberanilohydroxamic acid (SAHA). Compounds 8, 10, 11 and 17 exhibited significant inhibitory effects on various cancer cell lines with GI50 values in the range of 0.02 to 0.35 μM which are 10-50 folds better than SAHA. In-vivo nude mice model indicated the anti-angiogenic potential of these acrylamides. This study has indicated the potential of 3-{4-[2-(1-Ethyl-2-methyl-1H-indol-3-yl)-ethyl-N-tert-butoxycarbonylsulfamoyl]-phenyl}-N-hydroxy-acrylamide (11, mean GI50 = 0.04 μM) as a lead molecule for further development as anti-cancer agent.