Oleanolic Acid Lactones as Effective Agents in the Combat with Cancers—Cytotoxic and Antioxidant Activity, SAR Analysis, Molecular Docking and ADMETox Profile

Oleanolic acid derivatives, specifically lactones (<b>2</b>-<b>8</b>) and bromolactones (<b>9</b>-<b>14</b>), were synthesised and evaluated for their cytotoxic, antioxidant, and pharmacokinetic profiles. The compounds were characterised using molecular docking simulations targeting the 1M17 protein, representing the EGFR tyrosine kinase domain. Compound <b>6</b> emerged as the most promising candidate, demonstrating strong interactions with residues critical for EGFR activity, such as LYS 721 and ASP 831. Biological assays revealed that compounds <b>6</b>, <b>2</b>, and <b>10</b> exhibited IC₅₀ values across various cancer cell lines in the micromolar range, with a favourable Selectivity Index. Antioxidant activity assays (CUPRAC and DPPH) highlighted compound <b>7</b> as the most substantial electron donor and compound <b>10</b> as the most influential radical scavenger. ADMETox analysis confirmed the favourable pharmacokinetic and safety profiles of the derivatives. These findings underscore the potential of the selected oleanolic acid derivatives as drug candidates for targeted cancer therapies, offering cytotoxic and antioxidant benefits. Despite their promising cytotoxic and antioxidant activities, translating oleanolic acid derivatives to clinical applications remains challenging due to their bioavailability and metabolic stability. Our findings highlight compound 6 as a leading candidate with enhanced activity, providing a foundation for further optimising and developing EGFR-targeted anticancer therapies.