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

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• 作者：Jiachen Wen^a ; Qun Niu^a ; Jiang Liu^a ; Yu Bao^b ; Jinyu Yang^a ; Shenglin Luan^a ; Yinbo Fan^a ; Dan Liu^a ; ^{sammyld@163.com" class="auth_mail" title="E-mail the corresponding author} ; Linxiang Zhao^a ; ^{linxiang.zhao@vip.sina.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Histone deacetylase inhibitor ; Thiol ; 3-Phenyl-1H-pyrazole-5-carboxamide ; Structure&ndash ; activity relationships
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：26
• 期：2
• 页码：375-379
• 全文大小：807 K

文摘

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 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-1H-pyrazole-5-carboxamide scaffold to achieve better HDAC inhibitors.