Thiazole-Linked N -Hydroxypropanamide Derivatives: Selective HDAC6 Inhibitors with Therapeutic Potential for Neurodegenerative Diseases

Authors:
Publisher website
Google Scholar
Abstract
HDAC6 is a promising therapeutic target for the treatment of cancer and neurodegenerative and inflammatory diseases. We have developed a thiazolyl alkyl hydroxamate scaffold as an HDAC6-selective inhibitor. Herein, we synthesized new thiazolyl hydroxamate derivatives to investigate the effects of aliphatic linker length and cap group rigidity on HDAC6 selectivity. N-Hydroxy-3-(2-(6-methoxynaphthalen-2-yl)thiazol-4-yl)propanamide (5h) was identified as a potent HDAC6 inhibitor (IC50 = 25.56 nM) with ∼500-fold selectivity over HDAC1. Docking and MD simulations revealed that the 6-methoxy-β-naphthalene cap of 5h stably occupies a hydrophobic pocket containing HDAC6-specific nonconserved residues, providing a rationale for novel HDAC6 inhibitor design. Treatment with 5h upregulated BDNF (exons I and IV), and other neurogenesis-related genes in neural progenitor cells. In vivo, 5h improved memory performance in scopolamine-treated memory-impaired mice in the passive avoidance test. These findings suggest that 5h enhances neuroplasticity-related pathways and warrants further investigation as a potential therapeutic candidate for neurodegenerative diseases.
Funding Information
  • Korea Dementia Research Center (RS-2025-02215774)
  • National Research Foundation of Korea (2022R1A6A1A03054419)
  • National Research Foundation of Korea (NRF-2022M3A9G8017838)
  • National Research Foundation of Korea (NRF-2022M3A9G8084563)

This publication has 78 references indexed in Scilit: