Synthesis, Characterization and Antitumor Assessments of Sulfonamide-1,2,4 Compounds With EGFR Inhibitory Potential: DFT Calculation, Molecular Docking, Molecular Dynamics, and MM/PBSA Approaches

Abstract

Sulfonamide-containing 1,2,4-triazole compounds (2a-2g) were synthesized and characterized using FTIR and NMR spectroscopy. Theoretical investigations were performed for compounds 2a, 2c, 2f, and 2g using the DFT/ B3LYP/6-311++G(d,p) method. The optimized geometries, IR, and NMR data for these compounds were obtained and compared with experimental ones. The results indicate the presence of intermolecular N-H & ctdot;O type hydrogen bonds, as also confirmed by molecular electrostatic potential (MEP) maps. The newly synthesized compounds were evaluated for their anticancer potential against the normal lung cell line [Beas2B (RRID: CVCL-0168)] and several lung cancer cell lines, including [A549 (ATCC: CCL-185), Calu1 (ATCC: HTB-54), H1650 (ATCC: CRL-5883), SCLC21H (RRID: CVCL-0024), and PC9 (RRID: CVCL-B260)]. Notably, compounds 2a and 2d exhibited significant anticancer activity, with Total Growth Inhibition (TGI) values ranging from 69.13 to 93.15 mu g/mL against cancer cells, while showing minimal cytotoxicity toward normal cells (TGI: 211.55 and 281.17 mu g/ mL, respectively). DNA-binding studies revealed that compounds 2a (Kb: 2.8 x 102 M-1) and 2d (Kb: 1.0 x 103 M-1) exhibited stronger interactions with CT-DNA compared to the others. Importantly, compound 2d showed stable and selective binding at the EGFR active site, as demonstrated by molecular docking, 100 ns molecular dynamics (MD) simulations, and MM/PBSA free energy analysis. These computational findings are consistent with the biological data, suggesting that compound 2d is a promising candidate for EGFR-targeted anticancer therapy.