Design, synthesis & structure-activity relationships of a new class of antihuman enterovirus D68 & A71 agents

Future Med Chem. 2018 Jun 1;10(11):1333-1347. doi: 10.4155/fmc-2017-0268. Epub 2018 May 10.

Abstract

Aim: No antiviral medications are currently approved to treat enterovirus (EV)-associated disease or prevent EV infection.

Methods: In this study, a series of probenecid derivatives were designed via a rational strategy and synthesized to obtain more potent anti-EV agents.

Results: Compounds 8 and 24 exhibited the most potent activity against EV D68 and A71, with half maximal effective concentration (EC50) values of 2.49/2.09 and 2.59/2.41 μM, respectively, and revealed a broad inhibition spectrum toward other EV strains, with high selectivity indices. Additionally, compounds 8 and 24 showed good stability in rat serum, with half-lives of 48.39 and 60.26 min, respectively.

Conclusion: Compounds 8 and 24 are the promising candidates for the development of new agents against EV D68 and A71 viruses.

Keywords: EV A71; EV D68; metabolic stability; optimization; probenecid derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacokinetics
  • Cell Line
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Enterovirus / drug effects*
  • Enterovirus Infections
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Probenecid / analogs & derivatives
  • Probenecid / chemical synthesis*
  • Probenecid / pharmacokinetics
  • Rats
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Probenecid