A novel series of sulfonamide derivatives, coupled with a salicylamide scaffold, was designed and synthesized. The structures of the synthesized compounds were established using <sup>1</sup>H NMR, <sup>13</sup>C NMR and high-resolution mass spectroscopy. The synthesized compounds were tested <i>in vitro</i> against five types of human cell lines. Two were breast adenocarcinoma, including the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231. The others were the colorectal adenocarcinoma Caco-2, the carcinoma HCT-116 and the immortalized retinal-pigmented epithelium, hTERT-RPE1. Nine sulfonamides were able to inhibit the growth of the four tested cancer cells. Compound <b>33</b> was the most active against the selected colon cancer (Caco-2 and HCT-116) subtypes, while compound <b>24</b> showed the best efficacy against the examined breast cancer (MCF-7 and MDA-MB-231) cells. The selectivity index introduced compounds <b>24</b> and <b>33</b> as having the best selectivity among the breast and colon subtypes, respectively. <i>In vitro</i> tubulin polymerization experiments and flow cytometric assays showed that compounds <b>24</b> and <b>33</b> led to cell cycle arrest at the G2/M phase in a dose-dependent manner by effectively inhibiting tubulin polymerization. Furthermore, the results of the molecular docking studies indicate that this class of compounds can bind to the colchicine-binding site of tubulin.