N-Substituted dihydropyridines as promising EGFR tyrosine kinase inhibitors against breast cancer: Design, synthesis, biological evaluation, docking, and molecular dynamics simulations

Breast cancer is a major health concern, chemotherapy and radiotherapy face ongoing challenges due to drug resistance and toxicity. EGFR is a key driver of tumorigenesis, and its amplification or mutation is common in breast cancer. Tyrosine kinase inhibitors (TKIs), such as erlotinib and lapatinib, inhibit the EGFR pathway by competitively binding to the adenosine triphosphate pocket of EGFR. The Hantzsch reaction is a versatile method for synthesizing dihydropyridine derivatives that exhibit a range of pharmacological effects. This study aims for the molecular design, synthesis, analysis, and biological screening of N-Substituted Hantzsch dihydropyridines for their potential as EGFR inhibitors. The results showed that synthesized compounds inhibited the proliferation of MCF-7 breast cancer cells and modulated the expression of genes involved in the PI3K/Akt signaling pathway, which is downstream events of EGFR. Among all the synthesized compounds, NHD-3, NHD-4, and NHD-5 displayed the most potent inhibitory activity against MCF-7 cells with IC50 value of 17.24 ± 1.23, 10.92 ± 1.03, and 07.34 ± 0.86 µM, respectively. The potent dihydropyridines derivatives were also screened for EGFRwt inhibition assay and among the three compounds tested, NHD-5 showed reasonably good inhibitory activity with an IC50 value of 20.10 ± 1.30 nM compared to a Lapatinib with IC50 value of 10.28 ± 1.01 nM. Molecular docking and molecular dynamics simulations were performed to provide insight into the binding modes, interactions, and stability of these compounds with EGFR