Antitumor Activity and Multi-Target Mechanism of Phenolic Schiff Bases Bearing Methanesulfonamide Fragments: Cell Cycle Analysis and a Molecular Modeling Study

Five phenolic Schiff bases (<b>7</b>-<b>11</b>) incorporating a fragment of methanesulfonamide were synthesized and evaluated for their efficacy as antitumor agents. Compounds <b>7</b> and <b>8</b> demonstrated the most potent antitumor action, with a positive cytotoxic effect (PCE) of 54/59 and 59/59 and a mean growth percentage (MG%) of 67.3% and 19.5%, respectively, compared with imatinib (PCE = 20/59 and MG% = 92.6%). The PCE values for derivatives <b>9</b>-<b>11</b> were 3/59, 4/59, and 4/59, respectively, indicating poor antitumor effect. Compound <b>8</b> exhibited the most significant efficacy, suppressing cell proliferation by an average of 50% at a dosage of 0.501 µM, in comparison with the reference drugs sorafenib (2.33 µM), gefitinib (2.10 µM), erlotinib (7.68 µM), and celecoxib (17.5 µM). Compounds <b>7</b> and <b>8</b> had substantial inhibitory effects on the human epidermal growth factor receptor 2 (HER2), with IC₅₀ values of 0.183 μM and 0.464 μM, respectively. Furthermore, they exhibited significant inhibition of the epidermal growth factor receptor (EGFR), with IC₅₀ values of 0.752 μM and 0.166 μM, respectively. Compound <b>8</b> exhibited the highest COX-2 inhibition (IC₅₀ = 12.76 μM). We performed molecular docking dynamic experiments to examine the precise interaction and structural prerequisites for the anticancer activity of derivatives <b>7</b> and <b>8</b> by targeting EGFR and HER2.