2. Academic Validation
  3. Discovery of tetrahydroisoquinoline derivatives as selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting activities and neuroprotective activities

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

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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