Discovery of tetrahydroisoquinoline derivatives as selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting activities and neuroprotective activities

  • Bioorg Med Chem Lett. 2026 Feb 17:136:130593. doi: 10.1016/j.bmcl.2026.130593.
Shiru Liu  1 ,  Baiyun Dang  1 ,  Zhiwen Kang  1 ,  Ru Wei  1 ,  Zhanyuan Yang  2 ,  Xiangxin Guo  2 ,  Feixiang Shao  2 ,  Zhen Li  3 ,  Liang Xing  4 ,  Jiadong Hu  5 ,  Xin Chen  6
Affiliations
  • 1. Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China.
  • 2. College of Medicinal and Chemical Engineering, Shaanxi A&F Technology University, Yangling, Shannxi 712100, PR China.
  • 3. Department of Student Affairs, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, PR China.
  • 4. Guangxi Key Laboratory of Urban Water Environment, College of Chemistry and Environmental Engineering, Baise University, Baise 533000, PR China. Electronic address: [email protected].
  • 5. College of Medicinal and Chemical Engineering, Shaanxi A&F Technology University, Yangling, Shannxi 712100, PR China. Electronic address: [email protected].
  • 6. Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China. Electronic address: [email protected].
PMID: 41713755 DOI: 10.1016/j.bmcl.2026.130593
Abstract

Recently, histone deacetylase 6 (HDAC6) has attracted considerable attention for its potential in treating neurodegenerative disorders. In this paper, a series of tetrahydroisoquinoline derivatives were designed and synthesized as selective HDAC6 inhibitors. 4-((7-chloro-3, 4-dihydroisoquinolin-2(1H)-yl)methyl)-3-fluoro-N-hydroxybenzamide (8g), the most promising compound, potently inhibited HDAC6 (IC50 = 7.0 nM) and exhibited >2000 ~ fold selectivity over HDAC1. Molecular simulation indicated its molecular basis of HDAC6 inhibition. In vitro, 8g showed no significant toxicity on rat dopaminergic pheochromocytoma PC-12 cells. Furthermore, we demonstrated that 8g induced neurite outgrowth and showed good neuroprotective activity in PC-12 cells. Our research provided a new promising structure for the development of HDAC6is against Alzheimer's disease.

Keywords
HDAC6 inhibitor; Neurite outgrowth; Neuroprotective; Selectivity; THIQ.
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