A series of hybrids containing the pharmacophores of the histone deacetylase (HDAC) inhibitor, SAHA, and the antioxidant ebselen were designed and synthesized as multi-target-directed ligands against Alzheimer's disease. An in vitro assay indicated that some of these molecules exhibit potent HDAC inhibitory activity and ebselen-related pharmacological effects. Specifically, the optimal compound 7f was found to be a potent HDAC inhibitor (IC = 0.037 μM), possessing rapid hydrogen peroxide scavenging activity and glutathione peroxidase-like activity (ν = 150.0 μM min) and good free oxygen radical absorbance capacity (value of ORAC: 2.2). Furthermore, compound 7f showed significant protective effects against damage induced by HO and the ability to prevent ROS accumulation in PC12 cells.
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