Targeting Colon Cancer Cells with Pyrazino‐Imidazolinone Derivatives: Synthesis, Molecular Docking, and in Vitro Evaluation of Anti‐Proliferative and Pro‐Apoptotic Activities

Abstract

AbstractWe report the synthesis, spectroscopic characterization, molecular docking and biological evaluation of nine pyrazino‐imidazolinone derivatives. These derivatives were evaluated for their anticancer activity against three cancer cell lines: 518A2 melanoma, HCT‐116, and HCT‐116 p53 knockout mutant colon carcinoma. The MTT assay was employed to assess their effectiveness. Among the nine compounds tested, four compounds (5 a, 5 d, 5 g, and 5 h) exhibited promising antiproliferative activity specifically against HCT‐116 p53‐negative cells (IC50 0.23, 0.20, 2.07 and 58.75 μM, respectively). Interestingly, treatment with the 3,4‐dimethoxyphenyl derivative 5a resulted in a significant increase (199 %) in caspase activity in HCT‐116 p53‐negative cells compared to untreated cells while the bromo‐pyrazine derivative 5d demonstrated (190 %) increase. These findings suggest that compounds 5a and 5 d induce p53‐independent apoptotic cell death. Additionally, in silico molecular docking studies with EGFR and tyrosinase proteins indicated that compounds 5 d and 5 e have the potential to bind to important anticancer drug targets.