Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: design, synthesis and biological evaluation as antiviral agents

Molecules. 2013 May 21;18(5):6057-91. doi: 10.3390/molecules18056057.

Abstract

In order to find novel antiviral agents, a series of allosteric MEK1 inhibitors were designed and synthesized. Based on docking results, multiple optimizations were made on the coumarin scaffold. Some of the derivatives showed excellent MEK1 binding affinity in the appropriate enzymatic assays and displayed obvious inhibitory effects on the ERK pathway in a cellular assay. These compounds also significantly inhibited virus (EV71) replication in HEK293 and RD cells. Several compounds showed potential as agents for the treatment of viral infective diseases, with the most potent compound 18 showing an IC₅₀ value of 54.57 nM in the MEK1 binding assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents* / chemical synthesis
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • Cell Line, Tumor
  • Coumarins
  • Enterovirus A, Human / physiology*
  • Enterovirus Infections / drug therapy*
  • Enterovirus Infections / enzymology
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / metabolism
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Coumarins
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human