Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 21, Pages 5718-5729Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.10.022
Keywords
Alzheimer's disease; Histone deacetylase inhibitors; Glutathione peroxidase-like activity; Antioxidant activities; Multi-target-directed ligands
Funding
- National Natural Science Foundation of China [21772241, 21302235]
- Guangdong High-Level Personnel of Special Support Program-Young Top-Notch Talent Project [2015TQ01R244]
- Guangzhou Pearl River New Star Fund Science and Technology Planning Project [201610010111]
- Fundamental Research Funds for the Central Universities [15ykpy04]
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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 (IC50 = 0.037 mu M), possessing rapid hydrogen peroxide scavenging activity and glutathione peroxidase-like activity (nu(0) = 150.0 mu M min(-1)) and good free oxygen radical absorbance capacity (value of ORAC: 2.2). Furthermore, compound 7f showed significant protective effects against damage induced by H2O2 and the ability to prevent ROS accumulation in PC12 cells.
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