Benzo[ <i>f</i> ]chromene Derivatives as Cytotoxic Agents: Design, Synthesis, Molecular Docking, and ADMET

A series of novel benzo-[<i>f</i>]-chromene derivatives, <b>4-14</b>, were successfully synthesized and structurally characterized using spectroscopic techniques, including IR, ¹H-NMR, and ¹³C-NMR. The antiproliferative activities of selected compounds were evaluated against three human cancer cell lines<b>HepG-2</b> (hepatocellular carcinoma), <b>HCT-116</b> (colorectal carcinoma), and <b>MCF-7</b> (breast cancer)using the MTT assay. Cytotoxic effects were compared to standard anticancer agents 5-Fluorouracil and Doxorubicin. Among the tested compounds, <b>7</b>, <b>9</b>, and <b>12</b> exhibited superior cytotoxicity across all three cell lines, outperforming the reference drugs. Structure-activity relationship (SAR) analysis suggested that fused heterocyclic moieties at the 2,3-position significantly enhanced anticancer activity. Furthermore, in silico molecular docking studies targeting the EGFR tyrosine kinase domain (PDB ID: <b>4HJO</b>) demonstrated that compound <b>12</b> and the reference ligand <i>AQ4</i> formed stable interactions with key active-site residues, suggesting a potential mechanism of action through <i>EGFR</i> inhibition that warrants further experimental validation. These findings suggest that the synthesized benzo-[<i>f</i>]-chromene derivatives, particularly benzo-[<i>f</i>]-chromenopyrimidine derivative <b>12</b>, represent promising lead candidates for further development pending validation of their proposed mechanism of action, warranting future biochemical and cellular validation.