Synthesis and biological evaluation of novel indole-pyrazoline hybrid derivatives as potential topoisomerase 1 inhibitors

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126925. doi: 10.1016/j.bmcl.2019.126925. Epub 2019 Dec 26.

Abstract

A series of novel indole-pyrazoline hybrid derivatives were designed, synthesized, and evaluated for topoisomerase 1 (Top1) inhibitory activity. Top1-mediated relaxation assays showed that our synthesized compounds had variable Top1 inhibitory activity. Among these compounds, 3-(5-(naphthalen-1-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1-(phenylsulfonyl)-1H-indole (6n) was found to be a strong Top1 inhibitor with better inhibitory activity than CPT and hit compounds. Our further experiments rationalized the mode of action for this new type of inhibitors, which showed no significant binding to supercoiled DNA.

Keywords: CPT; Indole-pyrazoline hybrid derivatives; Supercoiled DNA; Topoisomerase 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • DNA Topoisomerases, Type I / chemistry*
  • DNA Topoisomerases, Type I / metabolism
  • DNA, Superhelical / chemistry
  • DNA, Superhelical / metabolism
  • Drug Design
  • Humans
  • Indoles / chemistry*
  • Molecular Dynamics Simulation
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis*
  • Topoisomerase I Inhibitors / metabolism

Substances

  • DNA, Superhelical
  • Indoles
  • Pyrazoles
  • Topoisomerase I Inhibitors
  • pyrazole
  • DNA Topoisomerases, Type I
  • TOP1 protein, human