2. Academic Validation
  3. Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer's disease

Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer's disease

  • Bioorg Chem. 2020 Oct;103:104109. doi: 10.1016/j.bioorg.2020.104109.
Feng He 1,  Yingying Ran 1,  Xiaoyang Li 2,  Defeng Wang 1,  Qiuqiong Zhang 1,  Jiahui Lv 1,  Chenggong Yu 1,  Ying Qu 1,  Xiangna Zhang 1,  Ana Xu 1,  Chao Wei 1,  C James Chou 3,  Jingde Wu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
  • 2 School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266071, PR China.
  • 3 Department of Drug Discovery and Biomedical Science, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States.
  • 4 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China. Electronic address: wujingde70@sdu.edu.cn.
PMID: 32768741 DOI: 10.1016/j.bioorg.2020.104109
Abstract

Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl-d-aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC50 of 0.18 μM and also maintains comparable activity on NMDAR (Ki = 0.59 μM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H2O2-induced cytotoxicity with EC50 of 0.94 μM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD.

Keywords

Alzheimer’s disease; HDACs inhibitor; Memantine moiety; NMDAR inhibitor; Neuroprotection.

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