To investigate the effect of isosteric replacement of phenyl with heteroaromatics of 4-phenyl-N-arylsulfonylimidazolones (1–4) as broad and potent anticancer agents, a series of 4-furyl (5a–e, 7a–c) or thienyl-N-arylsulfonylimidazolones (6a–e) were designed and synthesized to evaluate their in vitro anticancer activity against HCT116, A549 and NCI-H460 cancer cell lines. Replacement of phenyl with furyl or thienyl slightly reduced the activity, however, these analogs showed comparable activity to doxorubicin. The thienyl analogs exhibited more potent activity than furyl analogs due to their more isosteric similarity with the phenyl moiety. In addition, the carbamate derivatives (5a–e and 6a–e) of both the analogs had better activities than the carbamoyl derivatives (7a–c). Therefore, the size and planarity of the aryl motif at 4-position of N-arylsulfonylimidazolones are crucial for their anticancer activity.