This study describes the synthesis of a series of chalcones, including pyrazole and α,β-epoxide derivatives, and evaluation of their cell growth inhibitory activity in three human tumor cell lines, as well as their lipophilicity using liposomes as a biomimetic membrane model. Structure-activity and structure-lipophilicity relationships were established for the synthetized chalcones. From this work, nine chalcones (3, 5, 9, 11, 15-19) showing suitable drug-like lipophilicity with potent growth inhibitory activity were identified, being the growth inhibitory effect of compounds 15-17 associated with a pronounced antimitotic effect. Compounds 15-17 affected spindle assembly and, as a consequence, arrested cells at metaphase in NCI-H460 cells, culminating in cell death. Amongst the compounds tested, compound 15 exhibited the highest antimitotic activity as revealed by mitotic index calculation. Moreover, 15 was able to enhance chemosensitivity of tumor cells to low doses of paclitaxel in NCI-H460 cells. The results indicate that 15 exerts its antiproliferative activity by affecting microtubules and causing cell death subsequently to a mitotic arrest, and thus has the potential for antitumor activity.