In this study, the main objective was to develop new pyrido[2,3-d]pyrimidine derivatives with improved anticancer activity. To achieve this, a novel series of pyrido[2,3-d]pyrimidine derivatives was synthesized and evaluated for their anticancer potential using both computational and experimental approaches. Molecular docking was performed to assess their binding affinity toward epidermal growth factor receptor, a protein overexpressed in prostate cancer. ADMET analyses were conducted to predict pharmacokinetic and toxicity profiles, which revealed overall favorable results. Based on the docking outcomes, five compounds with the highest binding affinities were selected for further biological evaluation. The cytotoxicity of these compounds was tested against PC-3 prostate cancer cells. Among them, compound 8e exhibited the most potent cytotoxic activity, with IC50 values of 35.60 ± 1.14, 14.02 ± 1.26, and 9.39 ± 1.23 mM after 24, 48, and 72 h of treatment, respectively, compared with doxorubicin (IC50 2 lM). The selectivity index (SI) of 8e against normal HDF cells was 1.23, 2.54, and 5.72 at the corresponding time points. Flow cytometry analysis revealed that compound 8e induced cell cycle arrest at the S phase, while apoptosis assay showed a significant increase in total apoptotic cells—from 5.78% in untreated cells to 44.78% after treatment. In conclusion, with strong cytotoxicity, pronounced activity over time, compound 8e may serve as a promising anticancer candidate.

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