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

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.