Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease

• Published in: European journal of medicinal chemistry Vol. 275; pp. 116624 - 116641
• Main Authors: Liang, Ting, Liu, Shiru, Dang, Baiyun, Luan, Xiaofa, Guo, Yifan, Steimbach, Raphael R., Hu, Jiadong, Lu, Long, Yue, Peiyu, Wang, Ruotian, Zheng, Meng, Gao, Jinming, Yin, Xia, Chen, Xin
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.09.2024; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; Chemistry, Medicinal; Dose-Response Relationship, Drug; HDAC6 inhibitor; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Molecular Structure; Multimechanism; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; PC12 Cells; Pharmacology & Pharmacy; Rats; Reactive Oxygen Species - metabolism; Science & Technology; Selectivity; Structure-Activity Relationship; Tetrahydrocarboline; Zebrafish; Selectivity; Tetrahydrocarboline; Alzheimer's disease; HDAC6 inhibitor; Multimechanism; ACTIVATION; DESIGN; ACETYLATION; HISTONE DEACETYLASE INHIBITORS
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116624

With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-β-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD. [Display omitted] •Potent and selective HDAC6 inhibitors based on tetrahydrocarboline scaffold for AD treatment.•Computational simulations suggested the key interactions between 15 and HDAC6 enzyme.•Biological activity evaluation suggested tetrahydro-β-carboline derivative 15 showed anti-AD activity by multi-mechanisms.•15 significantly attenuated anxiety-like behaviour and memory deficit in a zebrafish model.