Tandem Synthesis and Computational Insights into Triazole and Pyrazole-Based Pyridine Derivatives Targeting EGFR-TK in Cancer Therapy

Cancer remains one of the leading causes of death worldwide, despite significant advances in treatment. Targeting tyrosine kinases, such as the epidermal growth factor receptor (EGFR), has become a promising approach for the development of anticancer agents. In this study, we designed and synthesized a series of triazole and pyrazole-based pyridine derivatives (<b>7a–c, 10a–c, 11, 14a,</b> and <b>14b</b>) to target EGFR-TK. Bioisosteric modifications were incorporated into these compounds, based on key pharmacophoric features of established EGFR-TK inhibitors. The compounds were evaluated for cytotoxicity against a range of cancer cell lines, including MCF-7, HepG2, HCT116, and EA hy926. Notably, compounds <b>14a</b> and <b>14b</b>, which feature the pyrazolo[3,4-b]pyridine-5-carbonitrile nucleus, demonstrated significant anticancer activity with lower IC₅₀ values across all tested cell lines. These compounds exhibited potent inhibitory effects, indicating their potential as effective EGFR-TK inhibitors. In silico studies, including ADME predictions, molecular docking, and molecular dynamics simulations, further supported their favorable pharmacokinetic profiles and strong binding interactions with EGFR-TK. Our findings suggest that these triazole and pyrazole-based pyridine derivatives could serve as promising candidates for the development of targeted anticancer therapies.