Synthesis and biological evaluation of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives as potential MERS-CoV inhibitors

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126727. doi: 10.1016/j.bmcl.2019.126727. Epub 2019 Oct 9.

Abstract

3-Acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives were synthesized and evaluated to show high anti-MERS-CoV inhibitory activities. Among them, 6,8-difluoro-3-isobutyryl-2-((2,3,4-trifluorophenyl)amino)quinolin-4(1H)-one (6u) exhibits high inhibitory effect (IC50 = 86 nM) and low toxicity (CC50 > 25 μM). Moreover, it shows good metabolic stability, low hERG binding affinity, no cytotoxicity, and good in vivo PK properties.

Keywords: 3-Acyl-2-amino-1,4-dihydroquinolin-4(1H)-ones; Inhibitor; MERS-CoV; RNA virus; SAR optimization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • CHO Cells
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Middle East Respiratory Syndrome Coronavirus / drug effects*
  • Molecular Structure
  • NIH 3T3 Cells
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Structure-Activity Relationship
  • Vero Cells

Substances

  • Antiviral Agents
  • Quinolones