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

Bioorg Med Chem Lett. 2016 Jan 15;26(2):375-379. doi: 10.1016/j.bmcl.2015.12.007. Epub 2015 Dec 7.

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.

Keywords: 3-Phenyl-1H-pyrazole-5-carboxamide; Histone deacetylase inhibitor; Structure–activity relationships; Thiol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • HeLa Cells
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Humans
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemistry*
  • Sulfhydryl Compounds / pharmacology*

Substances

  • Histone Deacetylase Inhibitors
  • Pyrazoles
  • Sulfhydryl Compounds
  • pyrazole-5-carboxamide
  • Histone Deacetylases