Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation

Eur J Med Chem. 2018 Feb 25;146:381-394. doi: 10.1016/j.ejmech.2018.01.068. Epub 2018 Feb 4.

Abstract

A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively.

Keywords: Anti-inflammatory activity; Butanehydrazides; Dual PDE4/7 inhibitors; Inflammation; Purine-2,6-dione; TNF-α inhibitors.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Butanes / analysis
  • Butanes / chemical synthesis
  • Butanes / chemistry
  • Butanes / pharmacology*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 7 / antagonists & inhibitors*
  • Cyclic Nucleotide Phosphodiesterases, Type 7 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Endotoxemia / drug therapy
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Male
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Purinones / chemical synthesis
  • Purinones / chemistry
  • Purinones / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Butanes
  • Hydrazines
  • Lipopolysaccharides
  • Phosphodiesterase Inhibitors
  • Purinones
  • butane
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclic Nucleotide Phosphodiesterases, Type 7