Antitumor Activity and Multi-Target Mechanism of Phenolic Schiff Bases Bearing Methanesulfonamide Fragments: Cell...

Five phenolic Schiff bases (7-11) incorporating a fragment of methanesulfonamide were synthesized and evaluated for their efficacy as antitumor agents. Compounds 7 and 8 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 9-11 were 3/59, 4/59, and 4/59, respectively, indicating poor antitumor effect. Compound 8 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 7 and 8 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 8 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 7 and 8 by targeting EGFR and HER2.