Design, Docking Analysis, and Structure–Activity Relationship of Ferrocene-Modified Tyrosine Kinase Inhibitors: Insights into BCR-ABL Interactions

Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds <b>6</b>, <b>9</b>, <b>14</b>, and <b>18</b>) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure-activity relationships. Compounds <b>6</b> and <b>9</b> demonstrated superior activity against the K-562 cell line, while compounds <b>14</b> and <b>18</b> exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds <b>9</b> and <b>14</b> toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target.