Synthesis and Evaluation of the Antiproliferative Effects of Pyrido[1’,2’:1,2]imidazo[5,4-d][1,2,3]triazinones on C6 Glioma Cells

Introduction: Imidazo[1,2-a]pyridine derivatives exhibit notable antitumor and other pharmacological activities. In this work, the imidazo[1,2-a]pyridine scaffold was functionalized with a triazinone pharmacophore, similar to that found in Temozolomide, which is responsible for its antitumor activity. Methods: A series of pyrido[1’,2’:1,2]imidazo[5,4-d][1,2,3]triazinone derivatives were synthesized. Their properties were predicted in silico using online platforms, such as Molinspiration, PASS Online, and OSIRIS Property Explorer, to identify the most promising candidates. The selected compounds were subsequently evaluated for anticancer activity against the C6 glioma cell line across six concentrations (0–1000 μM) to generate dose–response profiles. Temozolomide was used as the reference drug. Results: Compared to Temozolomide, compound 7a exhibited the highest activity with a CC50 (Citotoxic Concentration 50) of 284 μM, whereas compound 7f (with an isopropyl R group) showed a CC50 of 310 μM, similar to Temozolomide 304 μM. Discussion: Three key factors influencing the antiglioma activity of imidazo[1,2-a]pyridine derivatives emerged from this study: electronic stabilization, charge density, and steric effects of the amide nitrogen, which govern the CC50. Conclusion: The study identified compound 7a as a potent candidate with comparable activity to Temozolomide. These findings support further development and optimization of pyrido[5,4- d]imidazo-1,2,3-triazinone derivatives as potential anticancer agents.