Mechanistic Study of Novel Chromone–Sulfonamide Derivatives as Potential Anticancer Agents: Integrating Molecular Simulation and DFT Analysis

ABSTRACT In this study, five novel flavone‐sulfonamide derivatives ( h1 – h5 ) were designed and synthesized based on the pharmacologically active scaffolds of flavones and sulfonamides. The structures of the compounds were characterized by 1 H/ 13 C NMR, HRMS, and melting point analysis. In vitro antiproliferative activity was evaluated against human cervical cancer cells (HeLa), murine melanoma cells (B16F10), and human hepatocellular carcinoma cells (HepG2). Among them, compound h5 exhibited the most potent activity against HeLa cells, with an IC 50 value of 1.85 μM. Confocal laser scanning microscopy and flow cytometry analyses indicated that h5 induced early apoptosis and caused cell cycle arrest at the S and G2/M phases in HeLa cells. Network pharmacology analysis suggested that h5 might exert its antitumor effects by modulating the PI3K/Akt signaling pathway, with PIK3CA, PIK3CB, and PIK3CD identified as potential targets. Molecular docking and 100 ns molecular dynamics simulations were performed to investigate the binding stability of h5 with PI3K isoforms, and RMSD, RMSF, and Rg analyses supported the structural stability of the complexes. Furthermore, density functional theory (DFT) calculations revealed the frontier molecular orbitals and electrostatic potential distributions of h5 , indicating that the flavone core and sulfonamide moiety may serve as key reactive sites. These findings provide theoretical and experimental support for the development of new flavone‐based candidates for cervical cancer therapy.