Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Wen, Jiachen; Niu, Qun; Liu, Jiang; Bao, Yu; Yang, Jinyu; Luan, Shenglin; Fan, Yinbo; Liu, Dan; Zhao, Linxiang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 2(2016)
• Page Start: 375
• Page End: 379
• Publication Date: 2016-01-15
• Subjects: Histone deacetylase inhibitor -- Thiol -- 3-Phenyl-1H-pyrazole-5-carboxamide -- Structure–activity relationships; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.12.007
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of novel thiol-based histone deacetylase (HDAC) inhibitors bearing 3-phenyl-1 H -pyrazole-5-carboxamide scaffold as surface recognition motif was designed, synthesized, and evaluated for their HDAC inhibition activity. Among them, 15j (IC50 = 0.08 μM) was identified as a better inhibitor than Vorinostat (IC50 = 0.25 μM) against total HDACs. In addition, Structure–activity relationships (SAR) analyses indicated that (i) compounds with different substituents on pyrazole N -1 position exhibited superior activities than those on pyrazole N -2 position, (ii) variation of functional groups on N -1′-alkyl chain terminus followed the trends of carboxyl group > hydroxyl group ≫ alkyl group, and (iii) methylation on pyrazole C -4 position diminished the HDAC inhibition activity. The SAR will guide us to further refine compounds bearing 3-phenyl-1 H -pyrazole-5-carboxamide scaffold to achieve better HDAC inhibitors.