Discovery of indole-piperazine derivatives as selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting activities and neuroprotective activities. (1st February 2023)

• Record Type: Journal Article
• Authors: Liang, Ting; Xie, Zhao; Dang, Baiyun; Wang, Jiayun; Zhang, Tongtong; Luan, Xiaofa; Lu, Tao; Cao, Chenyu; Chen, Xin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 81(2023)
• Publication Date: 2023-02-01
• Subjects: HDAC6 inhibitor -- Indole-piperazine -- Selectivity -- Neurite outgrowth -- Neuroprotective; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2023.129148
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Potent and selective HDAC6 inhibitors based on the indole-piperazine scaffold. Computational simulations suggested the key interactions between representative 9c and HDAC6. 9c exhibited promising neurite outgrowth-promoting activity and neuroprotective activity. Abstract: Novel indole-piperazine derivatives with a hydroxamic acid moiety were designed and synthesized as selective histone deacetylase 6 (HDAC6) inhibitors. In enzymatic assays, all compounds exhibited nanomolar IC50 values. N -hydroxy-4-((4-(7-methyl-1 H -indole-3-carbonyl)piperazin-1-yl)methyl)benzamide, 9c, was the most potent HDAC6 inhibitor (IC50, 13.6 nM). In vitro, 9c induced neurite outgrowth of PC12 cells without producing toxic effects, better than Tubastatin A (Tub A). Additionally, 9c demonstrated blatant neuroprotective activity in PC12 cells against H2 O2 -induced oxidative damage. In western blot assay, 9c could increase the acetylation of α -tubulin in a dose-dependent manner.