A simple synthesis of sulfonamides 4–22 as novel histone deacetylase (HDAC) inhibitors is described. The key synthetic strategies involve N–sulfonylation of L–proline benzyl ester hydrochloride (2) and coupling reaction of N–sulfonyl chloride 3 with amines in high yields. It was found that several compounds showed good cellular potency with the most potent compound 20 exhibiting an IC50 = 2.8 μM in vitro.