Synthesis of Sulfonamide-Based Schiff Bases as Potent Anticancer Agents: Spectral Analyses, Biological Activity, Molecular Docking, ADME, DFT, and Pharmacophore Modelling Studies

The current study focuses on the synthesis and characterization of six benzenesulfonamide-based Schiff base derivatives (7–12) with various electron-withdrawing and electron-donating substituents (−F, -CI, -Br, −CH3, and −OCH3) and the assessment of their antiproliferative activities against human lung (A549) and liver (HepG2) cancer cell lines using in vitro and in silico approaches. The structures of the synthesized compounds (7–12) were elucidated by elemental analysis and FT-IR, 1D (1H, 13C, APT, and DEPT-135), and 2D (HMQC and HMBC) NMR spectroscopies. The cytotoxic activities of the targeted compounds were determined at various concentrations against these cancer cell lines for 72 h, using the MTT method. The targeted molecules (7–12) demonstrated remarkable antiproliferative activities, with IC50 values ranging from 6.032–9.533 μM against the A549 cell line and 5.244–9.629 μM against the HepG2 cell line. These compounds showed activities at lower or very similar concentrations to cisplatin against the A549 cell line and at much lower concentrations than cisplatin against the HepG2 cell line. Among them, compounds 10 and 12 were found to be more effective against A549 and HepG2 cells, respectively, than cisplatin. These compounds were analyzed by interacting with the 1BNA, 4HJO, and 4ASD crystal structures in molecular docking studies. The docking score of 4ASD-compound 12 interaction was calculated as −4.045 kcal/mol, 4HJO-compound 10 interaction was calculated as −5.179 kcal/mol and 1BNA-compound 10 interaction was calculated as −8.571 kcal/mol and it was determined that these compounds were theoretically better than Cisplatin. In the present study, ADME data were estimated using the web tool SwissADME. With ADME, it was calculated that the logP value of compounds 7–12 was less than 5, the HBD number was 1, the HBA number was 7 or 8, and the molecular weight was less than 500. Properties such as the electrophilic index and chemical hardness of the designed compounds were examined by density functional theory (DFT) using B3LYP/6-311G**. In conclusion, these compounds have emerged as promising new anti-cancer drug candidates. © 2024 Wiley-VHCA AG, Zurich, Switzerland.