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

  • J Med Chem. 2026 Jun 25;69(12):14140-14155. doi: 10.1021/acs.jmedchem.5c03292.
Gibeom Nam  1 ,  Jun Min Jung  1 ,  Seyun Yang  1 ,  Da Eun Kim  1 ,  Pulla Reddy Boggu  1 ,  Cheolhee Kim  2 ,  Eunae Kim  2 ,  Chanhee Jo  3 ,  Hyun-Mo Yang  1  4 ,  Jihun Kim  1 ,  Choon-Gon Jang  1 ,  Sang J Chung  1 ,  Jae Hoon Sul  1 ,  Dong-Gyu Jo  1 ,  Young Hoon Jung  1 ,  Hyun-Ju Park  1
Affiliations
  • 1. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, South Korea.
  • 2. College of Pharmacy, Chosun University, Gwangju 61452, South Korea.
  • 3. Epicure Inc., Gyeonggi-Biocenter 147, Suwon, Gyeonggi-do 16229, South Korea.
  • 4. Chong Kun Dang Research Institute, CKD Pharmaceuticals, Yongin-si, Gyeonggi-do 16995, South Korea.
PMID: 42241502 DOI: 10.1021/acs.jmedchem.5c03292
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.

Products