d-2-Hydroxyglutarate (d-2HG) is frequently found in human brain cancers. Approximately 50-80% of grade II glioma patients have a high level of d-2HG production, which can lead to cancer initiation. In this study, a series of novel 5-hydroxy-2-methyl-4<i>H</i>-pyran-4-one derivatives were designed and synthesized as antiglioma agents, and their related structure-activity relationships are discussed. Among these novel compounds, <b>4a</b> exhibited promising anti-proliferative activity against glioma HT1080 cells and U87 cells with an IC<sub>50</sub> of 1.43 μM and 4.6 μM, respectively. Further studies found that the most active compound (<b>4a</b>) shows an 86.3% inhibitory rate against the intracellular production of d-2HG at 1 μM, and dramatic inhibitory effects, even at 1 μM on the colony formation and migration of U87 and HT1080 cells.