Development of novel pyrimidine-thio-triazoles targeting EGFR in breast Cancer cells via one-pot copper-catalyzed 1,3-dipolar cycloaddition

Heterocycles are vital in medicinal chemistry due to their diverse pharmacological activities against various diseases. The development of innovative synthetic methods for heterocycles is ongoing, aiming to explore their full therapeutic potential. The epidermal growth factor receptor (EGFR) is a key target in breast cancer (BC) treatment due to its significant role in disease progression. This study aims to develop novel heterocyclic compounds containing benzimidazole, pyrimidine, and triazole derivatives, designed to target EGFR in breast cancer cells. The synthesis of the heterocyclic compounds was carried out using a one-pot CuI-catalyzed aryl amination followed by a Huisgen 1,3-dipolar cycloaddition reaction. The cytotoxic effects of the synthesized compounds were assessed using IC 50 assays against MCF-7 breast cancer cells, with Tamoxifen and Doxorubicin as internal controls. Molecular docking studies were conducted to explore the binding interactions within the EGFR ATP-binding site. Further, molecular dynamics (MD) simulations were performed for 100 ns to validate the stability and interactions of the active compounds. Compounds 6a and 6b demonstrated significant cytotoxic activity with IC 50 values of 29.62 μM and 41.8 μM, respectively. In silico docking revealed that both compounds fit well into the ATP-binding site of EGFR, showing binding affinities of −7.27 kcal/mol for 6a and − 7.45 kcal/mol for 6b . MD simulations confirmed the stability of these interactions, with 6a forming a more stable complex, suggesting its potential as a more effective EGFR inhibitor. The newly synthesized heterocyclic compounds exhibit potent cytotoxic effects against MCF-7 breast cancer cells and strong binding affinities to EGFR, indicating their potential as therapeutic agents. These findings warrant further investigation and optimization through preclinical and clinical studies to enhance their therapeutic efficacy against breast cancer. • Novel pyrimidine-thio-triazoles were synthesized using a one-pot CuI-catalyzed aryl amination and Huisgen 1,3-dipolar cycloaddition. • The synthetic methodology highlights high efficiency, enabling rapid access to the products. • Compounds 6a and 6b showed cytotoxic effects on MCF-7 cells with IC-50 values of 29.62 μM and 41.8 μM respectively. • In silico studies confirm EGFR binding affinity, validated by molecular dynamics. • These compounds warrant further preclinical studies as potential EGFR inhibitors for breast cancer treatment.