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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound <b>10,</b> and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds <b>16a–h</b> were discussed. The antiproliferative activity of <b>16a</b>–<b>h</b> was evaluated against three cancer (MCF7, A2780 and HT29, IC₅₀ = 0.01–40.50 μM) and one normal MRC5 (IC₅₀ = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for <b>16g</b> (IC₅₀ = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound <b>16g</b> revealed a cell cycle arrest at the G₂/M phase. In addition, compound <b>16g</b> induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound <b>16g</b> showed six potential targets that could mediate these activities. Molecular docking analysis of compound <b>16g</b> revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound <b>16g</b> with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for <b>16g</b> to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound <b>16g</b> as a potential anticancer agent.