We reported the synthesis of 25 derivatives of hydroxyaurone, which were characterized by H-1 NMR, C-13 NMR, high resolution mass spectrum, and single crystal X-ray diffraction analysis. Their activities on the death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) were evaluated by kinase detection kit at a dosage of 5 mu M. Most of the synthetic hydroxyaurones exhibited moderate to good inhibitory activities. The IC50 value ranged from 0.81 to 2.42 mu M when the structure of aurone's B ring was kept unchanged and its A ring was substituted by hydroxyl groups. On the contrary, modification of the aurone's B-ring with hydroxyl groups lead to the IC50 value ranging from 1.15 to 17.5 mu M. This indicates presence of hydroxyl group of the B ring is crucial for aurone's DRAK2 kinase inhibitors. Therefore, hydroxyaurone may serve as a new possible lead compound for the discovery of DRAK2. Further pharmacological investigations are underway and will be reported in due course.