Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2706-12. doi: 10.1016/j.bmcl.2016.04.002. Epub 2016 Apr 5.

Abstract

We report on an extensive structure-activity relationship study of novel PI4K IIIβ inhibitors. The purine derivative of the potent screening hit T-00127-HEV1 has served as a suitable starting point for a thorough investigation of positions 8 and 2. While position 8 of the purine scaffold can only bear a small substituent to maintain the inhibitory activity, position 2 is opened for extensive modification and can accommodate even substituted phenyl rings without the loss of PI4K IIIβ inhibitory activity. These empirical observations nicely correlate with the results of our docking study, which suggests that position 2 directs towards solution and can provide the necessary space for the interaction with remote residues of the enzyme, whereas the cavity around position 8 is strictly limited. The obtained compounds have also been subjected to antiviral screening against a panel of (+)ssRNA viruses.

Keywords: Antiviral agent; Hepatitis C virus; PI4K IIIβ; Phosphatidylinositol 4-kinase; Purine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Enterovirus B, Human / drug effects*
  • HeLa Cells
  • Hepacivirus / drug effects*
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / chemical synthesis
  • Purines / chemistry
  • Purines / pharmacology*
  • Rhinovirus / drug effects*
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Protein Kinase Inhibitors
  • Purines
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol 4-kinase IIIbeta, human
  • purine