Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors

Histone deacetylases (HDAC) regulate post-translational acetylation and the inhibition of these enzymes has emerged as an intriguing disease therapeutic. Among them, class IIb HDAC6 has the unique characteristic of mainly deacetylating cytoplasmic proteins, suggesting clinical applications for neurodegenerative diseases, inflammation, and cancer. In this study, we designed a novel N-benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide 4u (HDAC6 IC50 = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1. Structure-activity relationship (SAR) and computational docking studies were conducted to optimize the triazole capping group. Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors.

 

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In this study, the researchers focused on the development of novel inhibitors for histone deacetylase 6 (HDAC6), an enzyme involved in the regulation of post-translational acetylation. Inhibiting HDAC6 has shown potential as a therapeutic approach for various diseases, including neurodegenerative diseases, inflammation, and cancer. HDAC6 is unique among HDAC enzymes as it primarily deacetylates cytoplasmic proteins.

The researchers designed a new scaffold called N-benzyltriazolyl-hydroxamate, taking inspiration from two known HDAC6 inhibitors, nexturastat A and tubastatin A. They synthesized 27 derivatives of this scaffold and evaluated their inhibitory activity against HDAC6.

Among the derivatives, compound 4u (3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide) demonstrated nanomolar inhibitory activity against HDAC6, with an IC50 value of 7.08 nM. Importantly, it exhibited 42-fold selectivity for HDAC6 over HDAC1, indicating its potential as a selective HDAC6 inhibitor.

To optimize the triazole capping group of the scaffold, the researchers conducted structure-activity relationship (SAR) studies and computational docking analyses. Docking analysis revealed that the capping group of compound 4u aligned with the conserved L1 pocket of HDAC6, which is associated with subtype selectivity.

Overall, this study explored the use of a triazole-based biaryl capping group and its substitution and orientation to design HDAC6-selective inhibitors. The findings provide insights into the rational design of compounds that selectively target HDAC6, which could have implications for the development of therapeutic interventions for neurodegenerative diseases, inflammation, and cancer.