Revealing the Anti-Cancer Potential of 1,2,3-Triazole-Isonicotinate Derivatives Targeting EGFR Kinase Inhibition in MCF-7 Cancer Cells: Design, Synthesis, Biological Evaluation, and <i>In Silico</i> Studies

Click chemistry was used to synthesize a new library of 1,2,3-triazole-isonicotinate derivatives <b>8</b>–<b>13</b> using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between mono- or bis 2,6-ethynylisonicotinate <b>3</b>,<b>4</b>, and aromatic azides derivatives <b>5</b>–<b>7</b> with high yields (89–96%). These compounds were evaluated for their antiproliferative activity against hepatocellular carcinoma (Hep-G2), breast cancer (MCF-7), and colon cancer (HCT-116) cell lines, alongside a healthy non-cancerous skin fibroblast cell line (BJ-1). As compared with the reference drug, all new triazole-isonicotinate compounds have significantly greater cytotoxicity against colon and breast cancer cells, while compounds <b>13</b> and <b>10</b> have moderate cytotoxicity against liver cancer cells. The molecular docking study correlates the compound’s biological activity with its ability to establish stable interactions with protein-ligand complexes in the relevant biological targets. Compound <b>13</b> demonstrated a strong ability to induce apoptosis and cause cell cycle arrest in MCF-7 cells, along with significant inhibitory activity against the epidermal growth factor receptor (EGFR). These preliminary findings suggest that 1,2,3-triazole-isonicotinate derivatives, particularly compound <b>13</b>, hold potential as candidates for further investigation as anticancer agents for breast cancer treatment.