Design, synthesis and bioactivity evaluations of 8-substituted-quinoline-2-carboxamide derivatives as novel histone deacetylase (HDAC) inhibitors

Bioorg Med Chem. 2023 May 1:85:117242. doi: 10.1016/j.bmc.2023.117242. Epub 2023 Mar 18.

Abstract

The inhibition of histone deacetylases (HDACs) has been considered a promising therapeutic strategy for treatment of many diseases, especially cancer. In the current study, a series of 8-substituted quinoline-2-carboxamide derivatives were designed and synthesized as potent HDAC inhibitors. The most potent compound 21 g (IC50 = 0.050 µM) exhibited 3-fold greater HDAC inhibitory activity compared to the known HDAC inhibitor Vorinostat (IC50 = 0.137 µM). Additionally, compound 21g exhibited low toxicity against normal cells(IC50 in HUVEC cell > 50 µM) and showed good liver microsomal stability, therefore, may serve as a new lead compound for further development.

Keywords: Anti-cancer; HDAC inhibitor; Quinoline derivativve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Design
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism
  • Hydroxyquinolines* / pharmacology
  • Molecular Docking Simulation
  • Quinolines* / pharmacology
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Antineoplastic Agents
  • Histone Deacetylases
  • Hydroxyquinolines
  • Quinolines
  • Histone Deacetylase 1