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- Title
Design, synthesis and neuroprotective biological evaluation of novel HDAC6 inhibitors incorporating benzothiadiazinyl systems as cap groups.
- Authors
Han, Bo; Gu, Xiu; Wang, Mengfei; Wang, Huihao; Sun, Niubing; Yang, Xuezhi; Zhang, Qingwei
- Abstract
Histone deacetylase 6 (HDAC6), as the key regulatory enzyme, plays an important role in the development of the nervous system. More and more studies indicate that HDAC6 has become a promising therapeutic target for CNS diseases. Herein we designed and synthesized a series of novel HDAC6 inhibitors with benzothiadiazinyl systems as cap groups and evaluated their activity in vitro and in vivo. Among them, compound 3 exhibited superior selective inhibitory activity against HDAC6 (IC50 = 5.1 nM, about 30‐fold selectivity over HDAC1). The results of docking showed that compound 3 can interact well with the key amino acid residues of HDAC6. Compound 3 showed lower cytotoxicity (20 μM to SH‐SY5Y cells, inhibition rate = 25.75%) and better neuroprotective activity against L‐glutamate‐induced SH‐SY5Y cell injury model in vitro. Meanwhile, compound 3 exhibited weak cardiotoxicity (10 μM hERG inhibition rate = 17.35%) and possess good druggability properties. Especially, compound 3 could significantly reduce cerebral infarction from 49.87% to 32.18%, and similar with butylphthalide in MCAO model, indicating potential clinical application prospects for alleviating ischemic stroke‐induced brain infarction.
- Subjects
BIOSYNTHESIS; CEREBRAL infarction; AMINO acid residues; HISTONE deacetylase; NERVOUS system; HYDROXAMIC acids
- Publication
Chemical Biology & Drug Design, 2024, Vol 103, Issue 5, p1
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.14556