To define the SAR, a series of novel N-arylsulfonylimidazolidinone derivatives were evaluated for their in vitro anticancer activity against five human tumor cell lines, including A549, COLO205, KATO III, K562, SK-OV-3 and murine leukemia (P288D1) cell line. Among them, N-(2-chloroacetyl)-6-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)-3,4-dihydroquinoline-1(2H)-carboxamide (4m) and N-cyclohexyl-6-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)-3,4-dihydroquinoline-1(2H)-carboxamide (4n) exhibited comparable in vitro anticancer activity to doxorubicin against A549, KATO III and K562 cell lines and gave superior xenographic results against NCI-H23 and SW620 cancer cell lines. Regarding the structure-activity relationship, two critical points were discovered; the steric congestion at 4-position of N-arylsulfonylimidazolidinone scaffold abolishes the activity and the bulkiness or hydrophobicity of acyl groups at 3,4-dihydroquinoline of 4, especially with carbamoyl moiety, enormously enhances the activity.