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Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (<b>7a–ad</b>) and variably substituted anilines (<b>8a–v</b>) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-<i>a</i>]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (<b>8q</b>), 4′-fluoro-3′-chloroaniline (<b>8r</b>), 4′-chloroaniline (<b>8s</b>) and 4′-bromoaniline (<b>8u</b>), displayed the greatest antiproliferative activity with mean IC_50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [³H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-<i>a</i>]pyrimidine system, which characterized compounds <b>7a–ad</b>, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds <b>8q</b> and <b>8r</b> had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound <b>8q</b> significantly inhibited HeLa cell growth in zebrafish embryos.