Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives

Eur J Med Chem. 2018 Sep 5:157:994-1004. doi: 10.1016/j.ejmech.2018.08.057. Epub 2018 Aug 23.

Abstract

We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC50 = 4.56-20.16 μM) than EPZ004777 (IC50 = 35.19 μM). Surprisingly, SIN was founded to be not as active (IC50 > 50 μM) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC50 = 6.33-29.98 μM), and compound 9a also exhibits acceptable cytotoxicity (CC50 > 200 μM), suggesting their promising potential to be leads for further development.

Keywords: Anti-Zika virus; EPZ004777; Methyltransferases; Sinefungin; Structure-activity relationships.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / pharmacology*
  • Structure-Activity Relationship
  • Zika Virus / drug effects*

Substances

  • Antiviral Agents
  • EPZ004777
  • Phenylurea Compounds
  • Adenosine
  • sinefungin