Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study

作者：Wen, Jiachen; Niu, Qun; Liu, Jiang; Bao, Yu; Yang, Jinyu; Luan, Shenglin; Fan, Yinbo; Liu, Dan^*; Zhao, Linxiang

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(2): 375-379.

DOI：10.1016/j.bmcl.2015.12.007

• Histone deacetylase inhibitor
• Thiol
• 3-Phenyl-1H-pyrazole-5-carboxamide
• Structure-activity relationships

A series of novel thiol-based histone deacetylase (HDAC) inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif was designed, synthesized, and evaluated for their HDAC inhibition activity. Among them, 15j (IC50 = 0.08 mu M) was identified as a better inhibitor than Vorinostat (IC50 = 0.25 mu M) 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-1H-pyrazole-5-carboxamide scaffold to achieve better HDAC inhibitors.

• 出版日期2016-1-15
• 单位沈阳药科大学