Isophthalic Acid-Based HDAC Inhibitors as Potent Inhibitors of HDAC8 from Schistosoma mansoni

Arch Pharm (Weinheim). 2017 Aug;350(8). doi: 10.1002/ardp.201700096. Epub 2017 Jun 22.

Abstract

Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest preference for SmHDAC8 over its human orthologue hHDAC8. Docking studies provided insights into the putative binding mode in SmHDAC8 and allowed rationalization of the observed selectivity profile.

Keywords: Docking studies; HDAC8; Histone deacetylase inhibitors; Schistosoma mansoni; Schistosomiasis.

MeSH terms

  • Animals
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases
  • Humans
  • Molecular Docking Simulation
  • Phthalic Acids / chemical synthesis
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology*
  • Repressor Proteins / antagonists & inhibitors*
  • Schistosoma mansoni / enzymology
  • Schistosomicides / chemical synthesis
  • Schistosomicides / chemistry
  • Schistosomicides / pharmacology*
  • Species Specificity

Substances

  • Histone Deacetylase Inhibitors
  • Phthalic Acids
  • Repressor Proteins
  • Schistosomicides
  • isophthalate
  • HDAC8 protein, human
  • Histone Deacetylases