title: Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study.
abstract: 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=0.08μM) was identified as a better inhibitor than Vorinostat (IC50=0.25μM) 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.
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jiachen
authors.initials: J
authors.lastname: Wen
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Niu
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Luan
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yinbo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
authors.forename: Linxiang
authors.initials: L
authors.lastname: Zhao
mesh_terms: D015195:Drug Design; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D011720:Pyrazoles; D013438:Sulfhydryl Compounds; C000594236:pyrazole-5-carboxamide; D006655:Histone Deacetylases
keywords: 3-Phenyl-1H-pyrazole-5-carboxamide; Histone deacetylase inhibitor; Structure–activity relationships; Thiol