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

Abstract

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 (7a–c, 10a–c, 11, 14a, and 14b) 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 14a and 14b, 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.