Design, synthesis and pharmacophoric model building of new 3-alkoxymethyl/3-phenyl indole-2-carboxamides with potential antiproliferative activity

Chem Biol Drug Des. 2017 Jul;90(1):64-82. doi: 10.1111/cbdd.12928. Epub 2017 Jan 31.

Abstract

Novel 3-alkoxymethyl/3-phenyl indole-2-carboxamide derivatives were synthesized and evaluated for their anticancer activity. Most of the tested compounds showed moderate to excellent activity against the tested cell lines (MCF7 and HCT116). 3-Phenyl substitution on indole with p-piperidinyl phenethyl 24a and p-dimethylamino phenethyl 24c exhibited anticancer activity against MCF7 with IC50 of 0.13 and 0.14 μm, respectively. Further mechanistic study of the most active compounds through their action on cell cycle showed disturbance in cell cycle progression and cell cycle arrest. For future development of this series of compounds, pharmacophore study was conducted which indicated that the enhancement of the activity could be achieved through the addition of acceptor or donating groups to the already-present indole nucleus.

Keywords: anticancer; cell cycle; indole; pharmacophore; synthesis.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Drug Design*
  • HCT116 Cells
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / toxicity
  • MCF-7 Cells
  • Models, Molecular*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / toxicity
  • Structure-Activity Relationship

Substances

  • 5-chloro-3-phenyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide
  • 5-chloro-N-(4-(dimethylamino)phenethyl)-3-phenyl-1H-indole-2-carboxamide
  • Amides
  • Antineoplastic Agents
  • Indoles
  • Piperidines