Aim: This research aimed to design and synthesize pyrido[2,3-d]pyrimidine derivatives (7a–l) with possible anticancer properties, targeting the epidermal growth factor receptor (EGFR) in prostate cancer. Methods and results: A new series of pyrido[2,3-d]pyrimidine derivatives (7a–l) were synthesized in high yields by refluxing intermediate 6, obtained through a two-step process, with various aromatic aldehydes in glacial acetic acid, and were characterized by FTIR, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectrometry. Molecular docking simulations were carried out to assess the binding energy and interaction of these compounds with EGFR, which is overexpressed in prostate cancer cells. Based on docking results, Compounds 7d, 7f, 7k, 7a, and 7h were selected for cytotoxicity testing on PC-3 prostate cancer cells. Compound 7d, with the best docking score (−10.38 kcal/mol), exhibited the strongest anticancer effect, with inhibitory concentration (IC50 ) values of 43.78, 37.13, and 32.92 μM at 24, 48, and 72 h, respectively, compared to doxorubicin with an IC 50 ≈ 2 μM. Additionally, Compounds 7a, 7f, 7h, and 7k showed moderate to low activity, with IC 50 values ranging from 70 to 160 μM at 48 h. Compound 7d showed a selectivity index (SI) between 1 and 2 when tested on normal NIH/3T3 cells. Mechanistic studies indicated that 7d induced G1 phase cell cycle arrest and apoptosis in PC-3 cells. In silico ADMET analysis also predicted favorable pharmacokinetic properties for Compounds (7a–l). Conclusion: According to in silico and in vitro findings, Compound 7d showed promising anticancer potential for prostate cancer. Nevertheless, more preclinical research is necessary, including in vivo validation and kinase inhibition assays, to confirm EGFR-target engagement, and evaluate the therapeutic potential of Compound 7d.

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