A heterocyclic molecule with significant activity against dengue virus

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1425-7. doi: 10.1016/j.bmcl.2009.01.031. Epub 2009 Jan 15.

Abstract

There are no specific approved drugs or vaccines for the treatment or prevention of infectious dengue virus and there are very few compounds known that inhibit the replication of this virus. This letter describes the concise synthesis of two uracil-based multifunctional compounds. One of these compounds (1) has strong activity against dengue virus. It also exhibits low activity against a few other RNA viruses, but is highly active against yellow fever virus, a related flavivirus. It is likely that the mechanism of action of the antiviral activity of this compound is through its inhibition of the enzyme, inosine monophosphate dehydrogenase (IMPDH). Molecular modeling studies reveal that the compound can have specific hydrogen bonding interactions with a number of amino acids in the active site of IMPDH, a stacking interaction with the bound natural substrate, IMP, and the ability to interfere with the binding of NAD(+) with IMPDH, prior to the hydration step.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Catalytic Domain / drug effects
  • Catalytic Domain / physiology
  • Dengue Virus / drug effects*
  • Dengue Virus / physiology
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacology
  • IMP Dehydrogenase / chemistry
  • IMP Dehydrogenase / metabolism
  • Protein Binding / drug effects
  • Protein Binding / physiology

Substances

  • Antiviral Agents
  • Heterocyclic Compounds
  • IMP Dehydrogenase