Abstract <p>This study reports evaluation of the earlier reported series of (<i>E</i>)-<i>N</i>-(2-aminophenyl)-3-(quinolin-4-yl)acrylamides as potential inhibitors of histone deacetylase 8 (HDAC8) with anti-colon cancer activities. The target compounds were synthesized via four-step procedure, starting with quinoline-4-carboxylic acid derivatives. All synthesized molecules were tested for HDAC8 inhibitory activity using in vitro enzymatic assays, and their antiproliferative effects were evaluated against HCT-116 and COLO 205 colon cancer cell lines using the MTT assay. Among the tested compounds, (2<i>E</i>)-<i>N</i>-(2-aminophenyl)-3-(2-phenylquinolin-4-yl)prop-2-enamide (<b>A</b>) was found to be the most potent HDAC8 inhibitor with an IC₅₀ of 4.23 µM, and compound <b>(</b>2<i>E</i>)-<i>N</i>-(2-Aminophenyl)-3-(3-ethyl-2-phenylquinolin-4-yl)prop-2-enamide was the least active (IC₅₀ = 23.43 µM). In terms of the antiproliferative activity, compound <b>A</b> again showed the strongest effect on HCT-116 cells (EC₅₀ 17.42 µM), whereas (2<i>E</i>)-<i>N</i>-(2-aminophenyl)-3-(2,3-dimethyl-6-nitroquinolin-4-yl)prop-2-enamide demonstrated significant efficacy against COLO 205 cells (EC₅₀ 12.77 µM). The molecular docking study using the crystal structure of HDAC8 (PDB ID: 1T69) provided evidence for the favourable binding interactions of compounds in the enzyme active site. These findings suggest that quinoline derivatives, particularly compound <b>A</b> represent promising lead scaffolds for the development of HDAC8-targeted anticolon cancer therapeutics.</p>