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An efficient synthesis of a series of uracil analogous was performed to obtain new potential anticancer agents. The cytotoxic effect of the synthesized derivatives was assessed in vitro against three cancer cell lines, namely hepatic cancer (HepG-2), colon cancer (HCT-116), and breast cancer (MCF-7). Among the tested compounds, 5, 11 and 15 stood as potent uracil derivatives with pan cytotoxicity against the 3 cell lines out-performing the reference compound 5-FU. Furthermore, selected compounds underwent thymidylate synthase (TS) enzyme inhibition assay and demonstrated effective inhibition of the enzyme's catalytic activity. Thereafter, flow cytometric apoptosis and protein expression of pro- and anti-apoptotic markers Bax, BCL-2, PI3K, and STAT1 proteins assays were performed employing the most active compound on the respective most responsive cell line and compounds demonstrated effectiveness in inducing apoptosis in the treated cell lines. Finally, in silico studies encompassing molecular docking and molecular dynamics studies were also conducted to predict the interaction mechanisms and stability of the active compounds within the active site of their biological target TS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work is protected under patent application (EG/P/2024/1425)., (Copyright © 2024. Published by Elsevier Inc.)