Antiproliferative activity of twenty one Michael adducts of aroylacrylic acids and cyclic amines (N-Me-piperazine, imidazole, 2-Me-imidazole, and indole) was tested toward five human tumor cell lines (HeLa, LS174, K562, FemX, MDA-MB-361) in vitro. Compounds exerted antiproliferative activity in the high to the single-digit micromolar concentrations, causing increase of the cell population fraction in S phase and apoptosis. N-Me-piperazine and imidazole derivatives of aroylacrylic acids substituted with bulky alkyl substituents (2,4-di-i-Pr-Ph-, 2,4,6-tri-Et-Ph-, or β-tetrahydronaphthyl-) showed the best potency, while indole adducts were proved as the inferior antiproliferative agents. Few compounds showed significant selectivity, tumor versus healthy cells, with selectivity index ~60 for the most selective congener. An unbiased in silico distinction between more and less potent compounds was obtained from 3D QSAR models derived by alignment-independent GRIND-2 descriptors.